Self-contained heating unit and drug-supply unit employing same

ABSTRACT

Heating units, drug supply units and drug delivery articles capable of rapid heating are disclosed. Heating units comprising a substrate and a solid fuel capable of undergoing an exothermic metal oxidation reaction disposed within the substrate are disclosed. These heating units can be actuated by electrical resistance, by optical ignition or by percussion. Drug supply units and drug delivery articles wherein a solid fuel is configured to heat a substrate to a temperature sufficient to rapidly thermally vaporize a drug disposed thereon are also disclosed.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/485,704, filed Jun. 16, 2009, which is a continuation-in-part of U.S.application Ser. No. 10/850,895 filed May 20, 2004 and is acontinuation-in-part of U.S. application Ser. No. 10/851,429 filed May20, 2004 and is a continuation-in-part of U.S. application Ser. No.10/851,883 filed May 20, 2004 and is a continuation-in-part of U.S.application Ser. No. 10/851,432 filed May 20, 2004. These applicationsclaim priority to U.S. provisional application Ser. No. 60/472,697entitled “Self-Contained Heating Unit and Drug-Supply Unit EmployingSame,” filed May 21, 2003, Hale et al. The entire disclosures of whichare hereby incorporated by reference. Any disclaimer that may haveoccurred during the prosecution of the above-referenced applications ishereby expressly rescinded, and reconsideration of all relevant art isrespectfully requested.

This invention was made with Government support under Grant No. R44NS044800, awarded by the National Institutes of Health. The Governmenthas certain rights in the invention.

FIELD

This disclosure relates to heating units capable of rapid heating and toarticles and methods employing such heating units.

INTRODUCTION

Self-contained heat sources are employed in a wide-range of industries,from food industries for heating food and drink, to outdoor recreationindustries for providing hand and foot warmers, to medical applicationsfor inhalation devices. Many self-contained heating sources are based oneither an exothermic chemical reaction or on ohmic heating. For example,self-heating units that produce heat by an exothermic chemical reactionoften have at least two compartments, one for holding a heat-producingcomposition and one for holding an activating solution. The twocompartments are separated by a frangible seal, that when broken allowsmixing of the components to initiate an exothermic reaction to generateheat. (see for example U.S. Pat. Nos. 5,628,304; 4,773,389; 6,289,889).This type of non-combustible, self-heating unit is suitable for heatingfood, drink, or cold toes and fingers, since the heat production isrelatively mild.

Another common source for self-contained heat is ohmic heating. In ohmicheating a current is passed through an electrically resistive materialto generate heat that is transmitted to an adjacent article. This modeof heat production has been employed to vaporize or heat a volatilesubstance, for example tobacco, for inhalation by a user. Cigaretteholders and pipe bowls having an electrical resistance coil to generateheat in order to volatilize tobacco flavors have been described (U.S.Pat. Nos. 2,104,266; 4,922,901; 6,095,143). Heating of drugs other thantobacco by ohmic heating have also been described. For example, WO94/09842 to Rosen describes applying a drug to an electrically resistivesurface and heating the surface to vaporize the drug for inhalation.Ohmic heating has the advantage of facilitating precise control of theenergy applied to determine the heat generated. However, in many ohmicheating systems, and in particular for small systems where limitedenergy is available, such as, for example, when using batteries, therecan be a substantial delay on the order of seconds or minutes betweenthe time heating is initiated and maximum temperature is achieved.Moreover, for small devices, such as for example, portable medicaldevices, where the power source comprises a battery, ohmic heating canbe expensive and bulky.

Another approach for providing a controlled amount of heat is usingelectrochemical interactions. Here, components that interactelectrochemically after initiation in an exothermic reaction are used togenerate heat. Exothermic electrochemical reactions include reactions ofa metallic agent and an electrolyte, such as a mixture of magnesiumgranules and iron particles as the metallic agent, and granularpotassium chloride crystals as the electrolyte. In the presence ofwater, heat is generated by the exothermic hydroxylation of magnesium,where the rate of hydroxylation is accelerated in a controlled manner bythe electrochemical interaction between magnesium and iron, which isinitiated when the potassium chloride electrolyte dissociates uponcontact with the liquid water. Electrochemical interactions have beenused in the smoking industry to volatilize tobacco for inhalation (U.S.Pat. Nos. 5,285,798; 4,941,483; 5,593,792).

The aforementioned self-heating methods are capable of generating heatsufficient to heat an adjacent article to several hundred degreesCelsius in a period of several minutes. There remains a need in the artfor a device capable of rapid heat production, i.e., on the order ofseconds and fractions of seconds, capable of heating an article towithin a defined temperature range, and which is suitable for use inarticles to be used by people.

SUMMARY

Certain embodiments include a heating unit comprising an enclosurecomprising a substrate having an exterior surface and an interiorsurface, wherein the substrate has a thickness in the range of 0.001 to0.020 inches; a layer of solid fuel covering an area of the interiorsurface of the substrate corresponding to an area of the exteriorsurface of the substrate to be heated, wherein the solid fuel layer hasa thickness in the range of 0.001 to 0.030 inches and wherein the solidfuel is configured to heat a portion of the exterior surface of the atleast one substrate to a temperature of at least 200° C. within 1 secondfollow ignition of the solid fuel; and an igniter disposed at leastpartially within the enclosure for igniting the solid fuel. In certainembodiments, within 1 second after ignition of the solid fuel, no morethan 10% of said area of the exterior surface has a temperature 50° C.to 100° C. less than the remaining 90% of said area of the exteriorsurface. Additionally, in certain embodiments, within 500 millisecondsafter ignition of the solid fuel, no more than 10% of said area of theexterior surface has a temperature 50° C. to 100° C. less than theremaining 90% of said area of the exterior surface. In certainembodiments, within 250 milliseconds after ignition of the solid fuel,no more than 10% of said area of the exterior surface has a temperature50° C. to 100° C. less than the remaining 90% of said area of theexterior surface. In certain embodiments, the thin layer of solid fuelhas a thickness in the range of 0.001 to 0.005 inches. In certainembodiments, the enclosure comprises more than one substrate. In certainembodiments, the substrate is a metal foil having a thickness in therange of 0.001 to 0.010 inches.

Certain embodiments include a heating unit, wherein the solid fuelcomprises a metal reducing agent and a metal containing oxidizing agent.In certain embodiments, the metal containing oxidizing agent is selectedfrom at least one of the following: MoO₃, KClO₄, KClO₃, and Fe₂O₃. Incertain embodiments, the metal reducing agent is selected from at leastone of the following: aluminum, zirconium, iron, and titanium. Incertain embodiments, the amount of metal reducing agent comprises from60% to 90% by weight of the total dry weight of the solid fuel. Incertain embodiments, the amount of metal reducing agent comprises from10% to 40% by weight of the total dry weight of the solid fuel.

Certain embodiments include a heating unit, wherein the solid fuelcomprises at least one additive material. In certain embodiments, theadditive material is selected from at least one of the following: a claygelling agent, nitrocellulose, polyvinylalcohol, diatomaceous earthyglass beads and a colloidal silica.

Certain embodiments include a heating unit, wherein the substrate has athickness in the range of 0.002 to 0.010 inches. In certain embodiments,the substrate has a thickness in the range of 0.002 to 0.005 inches.

Certain embodiments include a heating unit, wherein the substrate is ametal, an alloy, or a ceramic.

Certain embodiments include a heating unit, wherein the ignitercomprises: an optical window in the enclosure; and a light sensitiveinitiator composition disposed within the enclosure. In certainembodiments, the initiator composition comprises a reducing agent and anoxidizing agent. In certain embodiments, the reducing agent of theinitiator composition is selected from at least one of the following:zirconium, titanium, and aluminum. In certain embodiments, the oxidizingagent of the initiator composition is selected from at least one of thefollowing: molybdenum trioxide, potassium perchlorate, copper oxide, andtungsten trioxide. In certain embodiments, the initiator compositioncomprises aluminum, boron, molybdenum trioxide, and a clay gellingagent.

Certain embodiments include a heating unit, wherein the substratecomprises a multi-layer structure. In certain embodiments, substrate isa polyimide, a polyester, or a fluoropolymer.

Certain embodiments include a heating unit, wherein the igniter is apercussive igniter. In certain embodiments, at least one impulseabsorbing material is disposed within the enclosure. In certainembodiments, a spacer provides an empty volume within the enclosure.

Certain embodiments include a heating unit, wherein at the least onesubstrate is a metal, an alloy, or a ceramic.

Certain embodiments include a heating unit, wherein the enclosure iscapable of withstanding an internal pressure of at least 50 psig.

Certain embodiments include a heating unit, wherein a drug layer is on aportion of the exterior surface of the at least one substrate.

Certain embodiments disclose methods of controlling uniformity oftemperature and peak temperature of a substrate surface by coating athin layer of a selected mass of a solid fuel on a surface of thesubstrate.

Certain embodiments include heating units comprising an enclosure and asolid fuel capable of undergoing an exothermic metal oxidation-reductionreaction disposed within the enclosure. The solid fuel in these heatingunits can be actuated using a variety of ignition systems.

Certain embodiments include drug supply units comprising an enclosurehaving at least one substrate having an exterior surface and an interiorsurface, a solid fuel capable of undergoing an exothermic metaloxidation-reduction reaction disposed within the enclosure, and a drugdisposed on a portion of the exterior surface of the substrate.

Certain embodiments include drug delivery devices comprising a housingdefining an airway, a heating unit comprising an enclosure having atleast one substrate having an exterior surface and an interior surface,and a solid fuel capable of undergoing an exothermic metaloxidation-reduction reaction disposed within the enclosure, a drugdisposed on a portion of the exterior surface of the substrate, whereinthe portion of the exterior surface comprising the drug is configured tobe disposed within the airway, and an igniter configured to ignite thesolid fuel.

Certain embodiments include methods of producing an aerosol of a drugand of treating a disease in a patient using such heating units, drugsupply units, and drug delivery devices.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of certain embodiments, as claimed.

DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B are cross-sectional illustrations of heating units accordingto certain embodiments.

FIG. 1C is a perspective illustration of a heating unit according tocertain embodiments.

FIG. 2A is a cross-sectional illustration of a heating unit having acylindrical geometry according to certain embodiments.

FIG. 2B is a perspective illustration of a heating unit having acylindrical geometry according to certain embodiments.

FIG. 2C is a cross-sectional illustration of a cylindrical heating unitsimilar to the heating unit of FIGS. 2A-2B but having a modified igniterdesign according to certain embodiments.

FIG. 2D is a cross-sectional illustration of a cylindrically-shapedheating unit that includes a thermal shunt according to certainembodiments.

FIG. 3 is a schematic cross-sectional illustration of a chemical heatingunit having two pressure transducers for measuring the internal pressureduring and after ignition of the solid fuel according to certainembodiments.

FIGS. 4A-4F are thermal images of a cylindrically-shaped heating unitmeasured using an infrared thermal imaging camera at post-ignition timesof 100 milliseconds (FIG. 4A), 200 milliseconds (FIG. 4B), 300milliseconds (FIG. 4C), 400 milliseconds (FIG. 4D), 500 milliseconds(FIG. 4E), and 600 milliseconds (FIG. 4F) according to certainembodiments.

FIGS. 5A-5B are thermal images showing the temperature uniformity of theexterior substrate surface expanse 400 milliseconds after ignition oftwo cylindrically-shaped heating units according to certain embodiments.

FIGS. 6A-6C show schematic illustrations of the generation of drug vaporfrom a drug supply unit carrying a film of drug on the exteriorsubstrate surface (FIG. 6A); ignition of the heating unit (FIG. 6B); andgeneration of a wave of heat effective to vaporize the drug film (FIG.6C) according to certain embodiments.

FIGS. 7A-7E are high speed photographs showing the generation of thermalvapor from a drug supply unit as a function of time following ignitionof the solid fuel according to certain embodiments.

FIG. 8 shows a drug delivery device containing a heating unit as part ofan inhalation drug delivery device for delivery of an aerosol comprisinga drug according to certain embodiments.

FIGS. 9A-9C show drug supply units for use in drug delivery devicesdesigned for delivering multiple drug doses according to certainembodiments.

FIGS. 10A-10B show illustrations of a perspective view (FIG. 10A) and anassembly view (FIG. 10B) of a thin film drug supply unit according tocertain embodiments;

FIGS. 11A-11B show cross-sectional illustrations of thin film drugsupply units comprising multiple doses according to certain embodiments.

FIG. 12 shows a relationship between the mass of a solid fuel coatingand the peak temperature of the exterior surface of a substrateaccording to certain embodiments.

FIG. 13A is an illustration of a cross-sectional view of a heating unithaving an impulse absorbing material disposed within the unit.

FIG. 13B is an illustration of a cross-sectional view of a cylindricalheating unit having an impulse absorbing material disposed within theunit.

FIG. 13C is an illustration of a cross-sectional view of a heating unithaving an impulse absorbing material and an additional pressure reducingelement disposed with the enclosure.

FIG. 14 shows the measured pressure within heating units comprisingglass fiber mats following ignition of the solid fuel.

FIG. 15 shows the temperature at various positions within a heating unitfollowing ignition of the solid fuel.

FIG. 16 is a schematic illustration of an igniter comprising aninitiator composition disposed on an electrically resistive heatingelement.

FIG. 17 shows peak internal pressure within sealed heating unitsfollowing ignition of a thin film layer of solid fuel comprising a metalreducing agent and a metal-containing oxidizer.

FIG. 18 shows the relationship of the yield and purity of an aerosolcomprising a specific pharmaceutical compound using different substratetemperatures obtained from different masses of solid fuel for variousembodiments.

FIG. 19 shows a temperature profile of a heating unit substratefollowing ignition of the solid fuel.

FIGS. 20A-D are schematic illustrations of various embodiments of singledose (FIGS. 20A, B and D) and multi-dose (FIG. 20C) heating unit with anoptical ignition system.

FIG. 21 is a schematic illustration of a heating unit with a percussionignition system.

DESCRIPTION OF VARIOUS EMBODIMENTS

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.”

In this application, the use of the singular includes the plural unlessspecifically stated otherwise. In this application, the use of “or”means “and/or” unless stated otherwise. Furthermore, the use of the term“including,” as well as other forms, such as “includes” and “included,”is not limiting. Also, terms such as “element” or “component” encompassboth elements and components comprising one unit and elements andcomponents that comprise more than one subunit unless specificallystated otherwise.

Heating Unit

An embodiment of a heating unit is shown in FIG. 1A. Heating unit 10 cancomprise a substrate 12 which can be formed from a thermally-conductivematerial. The substrate can be formed from a thermally-conductivematerial. Thermally-conductive materials are well known, and typicallyinclude, but are not limited to, metals, such as aluminum, iron, copper,stainless steel, and the like, alloys, ceramics, and filled polymers.The substrate can be formed from one or more such materials and incertain embodiments, can have a multilayer structure. For example, thesubstrate can comprise one or more films and/or coatings and/or multiplesheets or layers of materials. In certain embodiments, portions of thesubstrate can be formed from multiple sections. In certain embodiments,the multiple sections forming the substrate of the heating unit can havedifferent thermal properties. A substrate can be of any appropriategeometry, the rectangular configuration shown in FIG. 1A is merelyexemplary. A substrate can also have any appropriate thickness and thethickness of the substrate can be different in certain regions.Substrate 12, as shown in FIGS. 1A & 1B, has an interior surface 14 andan exterior surface 16. Heat can be conducted from interior surface 14to exterior surface 16. An article or object placed adjacent or incontact with exterior surface 16 can receive the conducted heat toachieve a desired action, such as warming or heating a solid or fluidobject, effecting a further reaction, or causing a phase change. Incertain embodiments, the conducted heat can effect a phase transition ina compound in contact, directly or indirectly, with exterior surface 16.

In certain embodiments, heating unit 10 can comprise an expanse of asolid fuel 20. Solid fuel 20 can be adjacent to the interior surface 14,where the term “adjacent” refers to indirect contact as distinguishedfrom “adjoining” which herein refers to direct contact. As shown in FIG.1A, solid fuel 20 can be adjacent to the interior surface 14 through anintervening open space 22 defined by interior surface 14 and solid fuel20. In certain embodiments, as shown in FIG. 1B, solid fuel 20 can be indirect contact with or adjoining interior surface 14. Solid fuels can beused to heat the substrates rapidly. The energy released during anexothermic reaction using solid fuels can be used to provide thetemperature rise required to heat directly or indirectly a materialadjacent to the exterior surface. In certain embodiments, the substrate12 has an expanse of a solid fuel 20, in direct contact with oradjoining interior surface 14.

The components of the solid fuel can react in an exothermic reaction toproduce heat. For example, the solid fuel can react in an exothermicoxidation-reduction reaction or an intermetallic alloying reaction. Anoxidation-reduction reaction refers to a chemical reaction in which onecompound gains electrons and another compound loses electrons. Thecompound that gains electrons is referred to as an oxidizing agent, andthe compound that loses electrons is referred to as a reducing agent. Anexample of an oxidation-reduction reaction is a chemical reaction of acompound with molecular oxygen (O₂) or an oxygen-containing compoundthat adds one or more oxygen atoms to the compound being oxidized.During the oxidation-reduction reaction, the molecular oxygen or theoxygen-containing compound is reduced by the compound being oxidized.The compound providing oxygen acts as the oxidizer or oxidizing agent.The compound being oxidized acts as the reducing agent.Oxidation-reduction reactions can be exothermic, meaning that thereactions generate heat. An example of an exothermic oxidation-reductionreaction is the thermite reaction of a metal with a metal oxidizingagent. In certain embodiments, a solid fuel can comprise a metalreducing agent and an oxidizing agent, such as for example, ametal-containing oxidizing agent.

In certain embodiments, a metal reducing agent can include, but is notlimited to molybdenum, magnesium, calcium, strontium, barium, boron,titanium, zirconium, vanadium, niobium, tantalum, chromium, tungsten,manganese, iron, cobalt, nickel, copper, zinc, cadmium, tin, antimony,bismuth, aluminum, and silicon. In certain embodiments, a metal reducingagent can include aluminum, zirconium, and titanium. In certainembodiments, a metal reducing agent can comprise more than one metalreducing agent.

In certain embodiments, an oxidizing agent can comprise oxygen, anoxygen based gas, and/or a solid oxidizing agent. In certainembodiments, an oxidizing agent can comprise a metal-containingoxidizing agent. In certain embodiments, a metal-containing oxidizingagent includes, but is not limited to, perchlorates and transition metaloxides. Perchlorates can include perchlorates of alkali metals oralkaline earth metals, such as, but not limited to, potassiumperchlorate (KClO₄), potassium chlorate (KClO₃), lithium perchlorate(LiClO₄), sodium perchlorate (NaClO₄), and magnesium perchlorate[Mg(ClO₄)₂]. In certain embodiments, transition metal oxides thatfunction as oxidizing agents include, but are not limited to, oxides ofmolybdenum, such as MoO₃, iron, such as Fe₂O₃, vanadium (V₂O₅), chromium(CrO₃, Cr₂O₃), manganese (MnO₂), cobalt (Co₃O₄), silver (Ag₂O), copper(CuO), tungsten (WO₃), magnesium (MgO), and niobium (Nb₂O₅). In certainembodiments, the metal-containing oxidizing agent can include more thanone metal-containing oxidizing agent.

In certain embodiments, the metal reducing agent forming the solid fuelcan be selected from zirconium and aluminum, and the metal-containingoxidizing agent can be selected from MoO₃ and Fe₂O₃.

The ratio of metal reducing agent to metal-containing oxidizing agentcan be selected to determine the ignition temperature and the burncharacteristics of the solid fuel. An exemplary chemical fuel cancomprise 75% zirconium and 25% MoO₃, percentage based on weight. Incertain embodiments, the amount of metal reducing agent can range from60% by weight to 90% by weight of the total dry weight of the solidfuel. In certain embodiments, the amount of metal-containing oxidizingagent can range from 10% by weight to 40% by weight of the total dryweight of the solid fuel. In certain embodiments, the amount ofoxidizing agent in the solid fuel can be related to the molar amount ofthe oxidizers at or near the eutectic point for the fuel composition. Incertain embodiments, the oxidizing agent can be the major component andin others the metal reducing agent can be the major component. Those ofskill in the art are able to determine the appropriate amount of eachcomponent based on the stoichiometry of the chemical reaction and/or byroutine experimentation. Also as known in the art, the particle size ofthe metal and the metal-containing oxidizer can be varied to determinethe burn rate, with smaller particle sizes selected for a faster burn(see, for example, U.S. Pat. No. 5,603,350).

In certain embodiments, a solid fuel can comprise additive materials tofacilitate, for example, processing and/or to determine the thermal andtemporal characteristics of a heating unit during and following ignitionof the solid fuel. An additive material can be reactive or inert. Aninert additive material will not react or will react to a minimal extentduring ignition and burning of the solid fuel. The additive can compriseinorganic or organic materials. In certain applications, particularly,where it is desirous to produce a minimal amount of gas, such as forexample, in a sealed heating unit, the additive material can beinorganic materials and can function as binders, adhesives, gellingagents, thixotropic agents, and/or surfactants. Examples of gellingagents include, but are not limited to, clays such as LAPONITE®,Montmorillonite, CLOISITE®, metal alkoxides, such as those representedby the formula R—Si(OR)_(n) and M(OR)_(n) where n can be 3 or 4, and Mcan be Ti, Zr, Al, B or other metals, and collidal particles based ontransition metal hydroxides or oxides. Examples of binding agentsinclude, but are not limited to, soluble silicates such as Na- orK-silicates, aluminum silicates, metal alkoxides, inorganic polyanions,inorganic polycations, and inorganic sol-gel materials, such as aluminaor silica-based sols.

In certain embodiments, the solid fuel comprises LAPONITE®, and inparticular LAPONITE® RDS, as an inert additive material. LAPONITE® is asynthetic layered silicate, and in particular a magnesiumphyllosilicate, with a structure resembling that of the natural claymineral hectorite (Na_(0.4)Mg_(2.7)Li_(0.3)Si₄O₁₀(OH)₂). LAPONITE® RD isa commercial grade material which, when added to water, rapidlydisperses to form a gel when hydrated (Southern Clay Products, Gonzales,Tex.). LAPONITE® RD has the following chemical analysis in weightpercent: 59.5% SiO₂:27.5% MgO:0.8% Li₂O:2.8% Na₂O. LAPONITE® RDS(Southern Clay Products, Gonzales, Tex.) is a commercially availablesol-forming grade of LAPONITE® modified with a polyphosphate dispersingagent, or peptizer, to delay rheological activity until the LAPONITE®RDS is added as a dispersion into a formulation. A sol refers to acolloid having a continuous liquid phase in which solid is suspended ina liquid. LAPONITE® RDS has the following chemical analysis in weightpercent: 54.5% SiO₂:26% MgO:0.8% Li₂O:5.6% Na₂O:4.1% P₂O₅, In thepresence of electrolytes, LAPONITEs® can act as gelling and thixotropicagents. Thixotropy refers to the property of a material to exhibitdecreased viscosity under shear.

When incorporated into a solid fuel composition comprising a metalreducing agent and a metal-containing oxidizing agent, such as any ofthose disclosed herein, in addition to imparting gelling and thixotropicproperties, LAPONITE® RDS can also act as binder. A binder refers to anadditive that produces bonding strength in a final product. The bindercan impart bonding strength, for example, by forming a bridge, film,matrix, and/or chemically self-react and/or react with otherconstituents of the formulation.

In certain embodiments, for example, when the solid fuel is disposed ona substrate as a film or thin layer, wherein the thickness of the thinlayer of solid fuel can range, for example, from 0.001 inches to 0.030inches, it can be useful that the solid fuel adhere to the surface ofthe substrate and that the constituents of the solid fuel adhere to eachother, and maintain physical integrity. In certain embodiments, it canbe useful that the solid fuel remain adhered to the substrate surfaceand maintain physical integrity during processing, storage, and useduring which time the solid fuel coating can be exposed to a variety ofmechanical and environmental conditions. Several additives, such asthose disclosed herein, can be incorporated into the solid fuel toimpart adhesion and physical robustness to the solid fuel coating.

In certain embodiments, small amounts of LAPONITE® RDS added to a solidfuel slurry comprising a metal reducing agent and a metal-containingoxidizing agent can impart thixotropic, gelling and in particular,adhesive properties to the solid fuel.

An example of the preparation of a solid fuel comprising LAPONITE® RDSand the application of the solid fuel to a metal foil substrate aredescribed in Example 1.

Other useful additive materials include glass beads, diatomaceous earth,nitrocellulose, polyvinylalcohol, and other polymers that may functionas binders. In certain embodiments, the solid fuel can comprise morethan one additive material. The components of the solid fuel comprisingthe metal, oxidizing agent and/or additive material and/or anyappropriate aqueous- or organic-soluble binder, can be mixed by anyappropriate physical or mechanical method to achieve a useful level ofdispersion and/or homogeneity. In certain embodiments, the solid fuelcan be degassed.

In addition to the enhanced binding properties of the solid fuels withadditive, other advantages of using inorganic additives includestability of the additive up to very high temperatures and lack of, orminimal release of, any toxic gases by the additive. In an enclosedsystem, this lack of additional gas production from the inorganicadditive also reduces or minimizes the possibility of rupture of theenclosed heating unit.

Tables 1A-1E summarize certain embodiments of solid fuel compositionsincluding the additives used. The weight ratio of the componentscomprising certain solid fuel compositions are provided.

TABLE 1A Embodiments of Solid Fuel Compositions (wt %) Component Fuel #1Fuel #2 Fuel #3 Fuel #4 Fuel #5 Fuel #6 Fuel #7 Fuel #8 Zirconium (Zr)70-90 20-40 20-30 Titanium (Ti) 70-92 60-80 Iron (Fe) 70-90 Magnesium(Mg) 20-40 40-60 Boron (B) 20-40 Potassium perchlorate 10-30  8-30 10-30(KClO₃) Lead Oxide (PbO) 40-60 Tungsten Oxide (WO₃) 60-80 BariumChromate 70-80 (BaCrO₄) Teflon 60-80

TABLE 1B Embodiments of Solid Fuel Compositions (wt %) Component Fuel #9Fuel #10 Fuel #11 Fuel #12 Fuel #13 Fuel #14 Fuel #15 Fuel #16 Zirconium(Zr) 21 10-50 Titanium (Ti) 60-80 70-92 82 55 33-81 Iron (Fe)  0-84Aluminum (Al) 20-40 20 Nickel (Ni) 60-80 Boron (B) 25 Potassiumperchlorate  8-30  9-17 50 (KClO₃) Potassium chlorate 18 (KClO₃)Tungsten Oxide (WO₃) 20-40 Barium Chromate 64 (BaCrO₄) Zirconium Carbide(ZrC) 50 Diatomaceous Earth 15

TABLE 1C Embodiments of Solid Fuel Compositions (wt %) Fuel Fuel FuelFuel Fuel Fuel Fuel Fuel Component #17 #18 #19 #20 #21 #22 #23 #24Zirconium (Zr) 50-65 50-72 30-80 65 55-70 Titanium (Ti) 20-70 Boron (B)15 Potassium 52.5 Perchlorate (KClO₄) Molybdenum  0-50 30-80 20-70 25-33Oxide (MoO₃) Iron Oxide  0-50 85 28-50 25 (Fe₂O₃) Zirconium 47.5 Hydride(ZrH₂) Diatomaceous balance 10  5-12 Earth

TABLE 1D Embodiments of Solid Fuel Compositions (wt %) Fuel Fuel FuelFuel Fuel Fuel Fuel Fuel Fuel Component #25 #26 #27 #28 #29 #30 #31 #32#33 Zirconium (Zr) 35-50 63-69 70 34 66.5-69 66.5-74.6   54-66.5 69 69Titanium (Ti) 20-35 Molybdenum Oxide 30   27-29.5 30 54 28.5-2924.87-29   28.5-34  29.85 29.85 (MoO₃) Nitrocellulose excess 0.53-4.5 0.5 0.5 Cab-O-Sil   4-7.5 Glass Fber 12 0.65 Glass Microsphere 0.65Polyvinyl Alcohol  2.5-4.5 High Vacuum Grease  5-12

TABLE 1E Embodiments of Solid Fuel Compositions (wt %) Fuel Fuel FuelFuel Fuel Fuel Fuel Fuel Fuel Fuel Component #34 #35 #36 #37 #38 #39 #40#41 #42 #43 Zirconium (Zr) 66.5-69 69.65 69.7-74.6 49-59.5 47-70 40 20Magnesium (Mg) 40 Aluminum (Al) 36-70 50-55 30 Silicon (Si) 30 Potassium0-3 chlorate (KClO₃) Bismuth Oxide 50 (Bi₂O₃) Molybdenum 28.5-29 29.8524.9-29.8 21-25.5 30-64 40 23.1-38   45-50 30 Oxide (MoO₃) Diatomaceous19-25   balance Earth or excess Nitrocellulose 0.5 0.4-2   1 Glass Beads20 Carboxymethyl excess cellulose Polyvinyl alcohol 0.5 40% Aqueous  2-5  SiO₂ VITON ®-A 0.5

While the use of additives in the solid fuel can improve the bindingproperties of the solid fuel, it also can improve the ease of use andmanufacturability of substrates coated with such fuel. In particular,use of additives can make it possible to use wet-coating techniques,such as, for example, but not limitation, dip coating, spray coating,roller coating, gravure coating, reverse roll coating, gap coating,metering rod coating, slot die coating, curtain coating, and air knifecoating, as means for deposition of a fuel powder on a substratesurface, such as, for example, either inside, or on, a cylindrical typesurface such as the internal surface of the substrate in FIG. 1C, or ona flat surface such as a foil as is shown in FIG. 10A.

The use of solid fuel slurries with additives for coating a substratecan provide for better mixing of the materials, enhanced adherenceproperties, and more control over the even disbursement of the solidfuel on a surface. While preparing a physical mixture of solid fuelpowders as an essentially homogeneous layer around the walls of acylindrical device can be done, it is problematic, especially if thematerials used have differences in densities, particle sizes, shapes,surface volume ratios, and lack chemically attractive surface-surfaceinteractions. (Essentially homogeneous is defined, for purposes herein,as essentially uniform; and when applied to a mixture of two or morecomponents, it refers to a basically uniform distribution of the variousdifferent particles throughout the mixture. This is in contrast to aheterogeneous mixture of components where various components tend toaggregate and there is settling out of the higher density particles.)Use of a core for dispersing mixtures of fuel powders to an interiorsurface of a substrate, allows one to control the gap or layer thicknessof the solid fuel layer; however, it does not prevent other problemssuch as segregation of the particles in the mixture. Inadequatehomogeneity as to the fuel mixture itself, due to ineffective mixing canresult in inconsistent heating of the exterior surface of the substrate.Mixing can be facilitated and even automated when done as a slurry asopposed to a dry powder.

Additionally, lack of homogeneity as to the fuel thickness on, or in,contact with an interior surface of a substrate can also result ininconsistent heating of the exterior surface of a substrate. Coatingadherence and ease of application can be enhanced by the use of slurrieswith additives.

In certain embodiments, the solid fuel is disposed on a substrate as acoating or thin layer, wherein the thickness of the thin layer of solidfuel can range, for example, from 0.001 inches to 0.030 inches by use ofwet coating

Substrates such as, for example, substrates 510 shown in FIG. 10A, canbe coated to a nearly homogeneous thickness to form a thin coating or athin layer of solid fuel 512 on the interior region of the substratecorresponding to the exterior surface on which the drug 514 is disposed.The thickness of the substrate, its thermal conductivity, its heatcapacity, the thickness of the thin layer of solid fuel 512, and thecomposition of solid fuel 512 can determine the maximum temperature(peak temperature) as well as the temporal and spatial dynamics of thetemperature profile produced by the burning of the solid fuel.

In certain embodiments, the metal reducing agent and the oxidizing agentcan be in the form of a powder. The term “powder” refers to powders,particles, prills, flakes, and any other particulate that exhibits anappropriate size and/or surface area to sustain self-propagatingignition. For example, in certain embodiments, the powder can compriseparticles exhibiting an average diameter ranging from 0.1 μm to 200 μm.

In certain embodiments, a solid fuel can comprise a multilayercomprising reactants capable of undergoing a self-sustaining exothermicreaction. A multilayer solid fuel comprising alternating and/orinterposed layers of materials capable of reacting exothermically, canbe continuous, or can be discontinuous. Each of the multiple layers canbe homogeneous or heterogeneous. A discontinuous layer refers to a layerthat can be patterned and/or have openings. The use of discontinuouslayers can increase the contact to the reactions; and by bringing thereactants into proximity, can thereby facilitate the exothermicreaction. Each layer can comprise one or more reactants, and cancomprise one or more additive materials such as binders, gelling agents,thixotropic agents, adhesives, surfactants, and the like.

The reacting layers can be formed into a multilayer structure by anyappropriate method that at least in part can be determined by thechemical nature of the reactants in a particular layer. In certainembodiments, metal foils or sheets of two or more reactants can be coldpressed/rolled to form a multilayer solid fuel. Multilayer solid fuelscan comprise alternating or mixed layers of reactants and can be formedby vapor deposition, sputtering or electrodeposition methods. Using wetcoating methods, multiple layers of dispersions comprising the reactantscan be deposited to form a multilayer solid fuel, wherein each layer cancomprise the same or different composition.

The number of layers and the thickness of each layer of reactants can beselected to establish the thermal and temporal characteristics of theexothermic reaction. Depending in part on the method used to form themultilayer solid fuel, the thickness of a layer can range from, forexample, 0.1 μm to 200 μm for a metal sheet, and can range from, forexample, 1 nm to 100 μm for a vapor- or electro-deposited layer. Thereactant layers can comprise elemental metals, alloys and/or metaloxides. Examples of layer pairs can include, but are not limited toAl:Ni, Al:Cu, Ti:Ni, Ti:C, Zr:B, Mo:Si, Ti:Si, and Zr:S. These and othercombinations of reactants and/or additive materials can be used tocontrol the burning characteristics of the solid fuel.

In certain embodiments, the multilayer structure can be repeatedlymechanically deformed to intermix the reactant layers. In certainembodiments, such as where layers are deposited by, for example, vapordeposition, sputtering or electrodeposition methods, the reactants canbe deposited to form an intermixed or heterogeneous composition.

In addition to the layers comprising reactants, a multilayer solid fuelstructure can comprise layers of non-reacting materials or materialshaving certain reaction properties to facilitate control of the thermaland temporal characteristics of the exothermic reaction.

In certain embodiments, a solid fuel can be machined, molded, preformedor packed. The solid fuel can be formed as a separate element configuredto be inserted into a heating unit, or the solid fuel can be applieddirectly to a heating unit. In certain embodiments, a solid fuel can becoated, applied, or deposited directly onto a substrate forming part ofa heating unit, onto a support that can be incorporated into a heatingunit, or onto a support configured to transfer the solid fuel to asubstrate forming a heating unit.

The solid fuel can be any appropriate shape and have any appropriatedimensions. For example, as shown in FIG. 1A, solid fuel 20 can beshaped for insertion into a square or rectangular heating unit. As shownin FIG. 1B, solid fuel 20 can comprise a surface expanse 26 and sideexpanses 28, 30. FIG. 1C illustrates an embodiment of a heating unit. Asshown in FIG. 1C, heating unit 40 comprises a substrate 42 having anexterior surface 44 and an interior surface 46. In certain embodiments,solid fuel 48, in the shape of a rod extending the length of substrate42 fills the inner volume defined by interior surface 46. In certainembodiments, solid fuel 48, is in the shape of a hollow rod extendingthe length of substrate 42 and exhibiting a diameter less than that ofinterior surface 46. In certain embodiments, the inner volume defined byinterior surface 46 can comprise an intervening space or a layer suchthat solid fuel 48 can be disposed as a cylinder adjacent interiorsurface 46, and/or be disposed as a rod exhibiting a diameter less thanthat of interior surface 46. It can be appreciated that a finned orribbed exterior surface can provide a high surface area that can beuseful to facilitate heat transfer from the solid fuel to an article orcomposition in contact with the surface.

In the various embodiments, fuel can be ignited to generate aself-sustaining oxidation-reduction reaction. Once a portion of thesolid fuel is ignited, the heat generated by the oxidation-reductionreaction can ignite adjacent unburned fuel until all of the fuel isconsumed in the process of the chemical reaction. The exothermicoxidation-reduction reaction can be initiated by the application ofenergy to at least a portion of the solid fuel. Energy absorbed by thesolid fuel or by an element in contact with the solid fuel can beconverted to heat. When the solid fuel becomes heated to a temperatureabove the auto-ignition temperature of the reactants, e.g. the minimumtemperature required to initiate or cause self-sustaining combustion inthe absence of a combustion source or flame, the oxidation-reductionreaction will initiate, igniting the solid fuel in a self-sustainingreaction until the fuel is consumed.

Energy can be applied to ignite the solid fuel using a number ofmethods. For example, a resistive heating element can be positioned inthermal contact with the solid fuel, which when a current is applied,can heat the solid fuel to the auto-ignition temperature. Anelectromagnetic radiation source can be directed at the solid fuel,which when absorbed, can heat the solid fuel to its auto-ignitiontemperature. An electromagnetic source can include lasers, diodes,flashlamps and microwave sources. RF or induction heating can heat thesolid fuel source by applying an alternating RF field that can beabsorbed by materials having high magnetic permeability, either withinthe solid fuel, or in thermal contact with the solid fuel. The source ofenergy can be focused onto the absorbing material to increase the energydensity to produce a higher local temperature and thereby facilitateignition. In certain embodiments, the solid fuel can be ignited bypercussive forces.

The auto-ignition temperature of a solid fuel comprising a metalreducing agent and a metal-containing oxidizing agent as disclosedherein can range of 400° C. to 500° C. While such high auto-ignitiontemperatures facilitate safe processing and safe use of the solid fuelunder many use conditions, for example, as a portable medical device,for the same reasons, to achieve such high temperatures, a large amountof energy must be applied to the solid fuel to initiate theself-sustaining reaction. Furthermore, the thermal mass represented bythe solid fuel can require that an impractically high temperature beapplied to raise the temperature of the solid fuel above theauto-ignition temperature. As heat is being applied to the solid fueland/or a support on which the solid fuel is disposed, heat is also beingconducted away. Directly heating a solid fuel can require a substantialamount of power due to the thermal mass of the solid fuel and support.

As is well known in the art, for example, in the pyrotechnic industry,sparks can be used to safely and efficiently ignite fuel compositions.Sparks refer to an electrical breakdown of a dielectric medium or theejection of burning particles. In the first sense, an electricalbreakdown can be produced, for example, between separated electrodes towhich a voltage is applied. Sparks can also be produced by ionizingcompounds in an intense laser radiation field. Examples of burningparticles include those produced by friction and break sparks producedby intermittent electrical current. Sparks of sufficient energy incidenton a solid fuel can initiate the self-sustaining oxidation-reductionreaction.

When sufficiently heated, the exothermic oxidation-reduction reaction ofthe solid fuel can produce sparks, as well as radiation energy. Thus, incertain embodiments, reliable, reproducible and controlled ignition ofthe solid fuel can be facilitated by the use of an initiator compositioncapable of reacting in an exothermic oxidation-reduction reaction. Theinitiator composition can comprise the same or similar reactants asthose comprising the solid fuel. In certain embodiments, the initiatorcomposition can be formulated to maximize the production of sparkshaving sufficient energy to ignite a solid fuel. Sparks ejected from aninitiator composition can impinge upon the surface of the solid fuel,causing the solid fuel to ignite in a self-sustaining exothermicoxidation-reduction reaction. The igniter can comprise a physicallysmall, thermally isolated heating element on which is applied a smallamount of an initiator composition capable of producing sparks or theinitiator composition can be placed directly on the fuel itself andignited by a variety of means, including, for example, optical orpercussive.

As shown in FIG. 1A, heating unit 10 can include an initiatorcomposition 50 which can ignite a portion of solid fuel 20. In certainembodiments, as shown in FIGS. 1A & 1B, initiator composition 50 can bepositioned proximate to the center region 54 of solid fuel 20. Initiatorcomposition 50 can be positioned at other regions of solid fuel 20, suchas toward the edges. In certain embodiments, a heating unit can comprisemore than one initiator composition where the more than one initiatorcomposition 50 can be positioned on the same or different side of solidfuel 20. In certain embodiments, initiator composition 50 can be mountedin a retaining member 56 that is integrally formed with substrate 12and/or secured within a suitably sized opening in substrate 12.Retaining member 56 and substrate 12 can be sealed to prevent releaseoutside heating unit 10 of reactants and reaction products producedduring ignition and burning of solid fuel 20. In certain embodiments,electrical leads 58 a, 58 b in electrical contact with initiatorcomposition 50 can extend from retaining member 56 for electricalconnection to a mechanism configured to activate (not shown) initiatorcomposition 50.

Initiator compositions capable of producing sparks upon exposure toheat, force, or a spark are known, for example, in the pyrotechnic fieldand the photoflash industry. In certain embodiments, an initiatorcomposition can comprise at least one metal, such as those describedherein, and at least one oxidizing agent, such as, for example, achlorate or perchlorate of an alkali metal or an alkaline earth metal ormetal oxide and others disclosed herein. In certain embodiments, aninitiator composition can include at least one binder and/or additivematerial such as a gelling agent and/or binder. Examples of additivematerials including gelling agents and/or binders are disclosed herein.In certain embodiments, additive materials can be useful in determiningcertain processing, ignition, and/or burn characteristics of theinitiator composition.

FIG. 2A shows a longitudinal cross-sectional illustration of anembodiment of a heating unit. FIG. 2B shows a corresponding perspectiveillustration of an embodiment illustrating the unassembled individualcomponents shown in FIG. 2A. As shown in FIG. 2A, heating unit 60 caninclude a substrate 62 that is generally cylindrical in shape andterminates at one end in a tapered nose portion 64 and at the other endin an open receptacle 66. Substrate 62 has interior and exteriorsurfaces 68, 70, respectively, which define an inner region 72. An innerbacking member 74 can be cylindrical in shape and can be located withininner region 72. The opposing ends 76, 78 of backing member 74 can beopen. In certain embodiments, backing member 74 can comprise aheat-conducting or heat-absorbing material, depending on the desiredthermal and temporal dynamics of the heating unit. When constructed of aheat-absorbing material, backing member 74 can reduce the maximumtemperature reached by substrate 62 after ignition of the solid fuel 80.

In certain embodiments, solid fuel 80 comprising, for example, any ofthe solid fuels described herein, can be confined between substrate 62and backing member 74 or can fill inner region 72. Solid fuel 80 canadjoin interior surface 68 of substrate 62.

In certain embodiments, initiator composition 82 can be positioned inopen receptacle 66 of substrate 62, and can be configured to ignitesolid fuel 80. In certain embodiments, a retaining member 84 can belocated in open receptacle 66 and can be secured in place using anysuitable mechanism, such as for example, bonding or welding. Retainingmember 84 and substrate 62 can be sealed to prevent release of thereactants or reaction products produced during ignition and burn ofinitiator composition 82 and solid fuel 80. Retaining member 84 caninclude a recess 86 in the surface facing inner region 72. Recess 86 canretain initiator composition 82. In certain embodiments, an electricalstimulus can be applied directly to initiator composition 82 via leads88, 90 connected to the positive and negative termini of a power source,such as a battery (not shown). Leads 88, 90 can be connected to anelectrically resistive heating element placed in physical contact withthe initiator composition 82 (not shown). In certain embodiments, leads88, 90 can be coated with the initiator composition 82.

Referring to FIG. 2A, application of a stimulus to initiator composition82 can result in the generation of sparks that can be directed from openend 78 of backing member 74 toward end 76. Sparks directed toward end 76can contact solid fuel 80, causing solid fuel 80 to ignite. Ignition ofsolid fuel 80 can produce a self-propagating wave of ignited solid fuel80, the wave traveling from open end 78 toward nose portion 64 and backtoward retaining member 84 held within receptacle end 66 of substrate62. The self-propagating wave of ignited solid fuel 80 can generate heatthat can be conducted from interior surface 68 to exterior surface 70 ofsubstrate 62.

An embodiment of a heating unit is illustrated in FIG. 2C. As shown inFIG. 2C, heating unit 60 can comprise a first initiator composition 82disposed in recess 86 in retaining member 84 and a second initiatorcomposition 94 disposed in open end 76 of backing member 74. Backingmember 74, located within inner region 72, defines an open region 96.Solid fuel 80 is disposed within the inner region between substrate 62and backing member 74. In certain embodiments, sparks generated uponapplication of an electrical stimulus to first initiator composition 82,through leads 88, 90, can be directed through open region 96 towardsecond initiator composition 94, causing second initiator composition 94to ignite and generate sparks. Sparks generated by second initiatorcomposition 94 can then ignite solid fuel 80, with ignition initiallyoccurring toward the nose portion of substrate 62 and traveling in aself-propagating wave of ignition to the opposing end.

In certain embodiments, the igniter can comprise a support and aninitiator composition disposed on the support. In certain embodiments,the support can be thermally isolated to minimize the potential for heatloss. In this way, dissipation of energy applied to the combination ofassembly and support can be minimized, thereby reducing the powerrequirements of the energy source, and facilitating the use ofphysically smaller and less expensive heat sources. In certainapplications, for example, with battery powered portable medicaldevices, such considerations can be particularly useful. In certainembodiments, it can be useful that the energy source be a small low costbattery, such as a 1.5 V alkaline battery. In certain embodiments, theinitiator composition can comprise a metal reducing agent andmetal-containing oxidizing agent.

In certain embodiments, a metal reducing agent can include, but is notlimited to molybdenum, magnesium, calcium, strontium, barium, boron,titanium, zirconium, vanadium, niobium, tantalum, chromium, tungsten,manganese, iron, cobalt, nickel, copper, zinc, cadmium, tin, antimony,bismuth, aluminum, and silicon. In certain embodiments, a metal reducingagent can include aluminum, zirconium, and titanium. In certainembodiments, a metal reducing agent can comprise more than one metalreducing agent. In certain embodiments, an oxidizing agent can compriseoxygen, an oxygen based gas, and/or a solid oxidizing agent. In certainembodiments, an oxidizing agent can comprise a metal-containingoxidizing agent. In certain embodiments, a metal-containing oxidizingagent includes, but is not limited to, perchlorates and transition metaloxides. Perchlorates can include perchlorates of alkali metals oralkaline earth metals, such as but not limited to, potassium perchlorate(KClO₄), potassium chlorate (KClO₃), lithium perchlorate (LiClO₄),sodium perchlorate (NaClO₄), and magnesium perchlorate [Mg(ClO₄)₂]. Incertain embodiments, transition metal oxides that function as oxidizingagents include, but are not limited to, oxides of molybdenum, such asMoO₃, iron, such as Fe₂O₃, vanadium (V₂O₅), chromium (CrO₃, Cr₂O₃),manganese (MnO₂), cobalt (Co₃O₄), silver (Ag₂O), copper (CuO), tungsten(WO₃), magnesium (MgO), and niobium (Nb₂O₅). In certain embodiments, themetal-containing oxidizing agent can include more than onemetal-containing oxidizing agent.

The ratio of metal reducing agent to metal-containing oxidizing agentcan be selected to determine the appropriate burn and spark generatingcharacteristics. In certain embodiments, the amount of oxidizing agentin the initiator composition can be related to the molar amount of theoxidizers at or near the eutectic point for the fuel composition. Incertain embodiments, the oxidizing agent can be the major component andin others the metal reducing agent can be the major component. Those ofskill in the art are able to determine the appropriate amount of eachcomponent based on the stoichiometry of the chemical reaction and/or byroutine experimentation. Also as known in the art, the particle size ofthe metal and the metal-containing oxidizer can be varied to determinethe burn rate, with smaller particle sizes selected for a faster burn(see, for example, PCT WO 2004/01396).

In certain embodiments, an initiator composition can comprise additivematerials to facilitate, for example, processing, enhance the mechanicalintegrity and/or determine the burn and spark generatingcharacteristics. The additive materials can be inorganic materials andcan function as binders, adhesives, gelling agents, thixotropic, and/orsurfactants. Examples of gelling agents include, but are not limited to,clays such as LAPONITE®, Montmorillonite, CLOISITE®, metal alkoxidessuch as those represented by the formula R—Si(OR)_(n) and M(OR)_(n)where n can be 3 or 4, and M can be Ti, Zr, Al, B or other metals, andcolloidal particles based on transition metal hydroxides or oxides.Examples of binding agents include, but are not limited to, solublesilicates such as Na- or K-silicates, aluminum silicates, metalalkoxides, inorganic polyanions, inorganic polycations, inorganicsol-gel materials such as alumina or silica-based sols. Other usefuladditive materials include glass beads, diatomaceous earth,nitrocellulose, polyvinylalcohol, guor gum, ethyl cellulose, celluloseacetate, polyvinyl-pyrrolidone, fluoro-carbon rubber (VITON®) and otherpolymers that can function as a binder. In certain embodiments, theinitiator composition can comprise more than one additive material. Thecomponents of the initiator composition comprising the metal,metal-containing oxidizing agent and/or additive material and/or anyappropriate aqueous- or organic-soluble binder, can be mixed by anyappropriate physical or mechanical method to achieve a useful level ofdispersion and/or homogeneity. In certain embodiments, additivematerials can be useful in determining certain processing, ignition,and/or burn characteristics of the initiator composition. In certainembodiments, the particle size of the components of the initiator can beselected to tailor the ignition and burn rate characteristics as isknown in the art (see for example U.S. Pat. No. 5,739,460 the disclosureof which is hereby incorporated by reference in its entirety).

In certain embodiments, an initiator composition can comprise at leastone metal, such as those described herein, and at least one oxidizingagent, such as, for example, a chlorate or perchlorate of an alkalimetal or an alkaline earth metal or metal oxide and others disclosedherein.

Examples of initiator compositions include compositions comprising 10%Zr:22.5% B:67.5% KClO₃; 49.) % Zr:49.0% MoO₃ and 2.0% nitrocellulose,and 33.9% Al:55.4% MoO₃:8.9% B:1.8 nitrocellulose; 26.5% Al:51.5%MoO₃:7.8% B:14.2% VITON®, in weight percent.

Other initiator compositions can be used. For example, an initiatorcomposition that can ignite upon application of a percussive forcecomprises a mixture of sodium chlorate (NaClO₃), phosphorous (P), andmagnesium oxide (MgO).

Energy sufficient to heat the initiator composition to the auto-ignitiontemperature can be applied to the initiator composition and/or thesupport on which the initiator composition is disposed. The energysource can be any of those disclosed herein, such as resistive heating,radiation heating, inductive heating, optical heating, and percussiveheating. In embodiments wherein the initiator composition is capable ofabsorbing the incident energy, the support can comprise a thermallyinsulating material. In certain embodiments, the incident energy can beapplied to a thermally conductive support that can heat the initiatorcomposition above the auto-ignition temperature by thermal conduction.

In certain embodiments, the energy source can be an electricallyresistive heating element. The electrically resistive heating elementcan comprise any material that can maintain integrity at theauto-ignition temperature of the initiator composition. In certainembodiments, the heating element can comprise an elemental metal such astungsten, an alloy such as Nichrome, or other material such as carbon.Materials suitable for resistive heating elements are known in the art.The resistive heating element can have any appropriate form. Forexample, the resistive heating element can be in the form of a wire,filament, ribbon or foil. In certain embodiments, the electricalresistance of the heating unit can range from 2Ω to 4Ω. The appropriateresistivity of the heating element can at least in part be determined bythe current of the power source, the desired auto ignition temperature,or the desired ignition time. In certain embodiments, the auto-ignitiontemperature of the initiator composition can range from 200° C. to 500°C. The resistive heating element can be electrically connected, andsuspended between two electrodes electrically connected to a powersource.

The support can comprise one or more heating units.

An embodiment of an igniter comprising a resistive heating element isillustrated in FIG. 16. As shown in FIG. 16, resistive heating element716 is electrically connected to electrodes 714. Electrodes 714 can beelectrically connected to an external power source such as a battery(not shown). As shown in FIG. 16, electrodes 714 are disposed on alaminate material 712 such as a printed circuit material. Such materialsand methods of fabricating such flexible or rigid laminated circuits arewell known in the art. In certain embodiments, laminate material 712 cancomprise a material that will not degrade at the temperatures reached byresistive heating element 716, by the exothermic reaction includingsparks generated by initiator composition 718, and at the temperaturereached during burning of the solid fuel. For example, laminate 712 cancomprise Kapton®, a fluorocarbon laminate material or FR4epoxy/fiberglass printed circuit board. Resistive heating element 716 ispositioned in an opening 713 in laminate 712. Opening 713 thermallyisolates resistive heating element 716 to minimize thermal dissipationand facilitate transfer of the heat generated by the resistive heatingelement to the initiator composition, and can provide a path for sparksejected from initiator composition 718 to impinge upon a solid fuel (notshown).

As shown in FIG. 16, initiator composition 718 is disposed on resistiveheating element 716.

The following procedure was used to apply the initiator composition toresistive heating elements.

A 0.0008 inch diameter Nichrome wire was soldered to Cu conductorsdisposed on a 0.005 inch thick FR4 epoxy/fiberglass printed circuitboard (Onanon). The dimensions of the igniter printed circuit board were1.82 inches by 0.25 inches. Conductor leads can extend from the printedcircuit board for connection to a power source. In certain embodiments,the electrical leads can be connected to an electrical connector.

The igniter printed circuit board was cleaned by sonicating (Branson8510R-MT) in DI water for 10 minutes, dried, sprayed with acetone andair dried.

The initiator composition comprised 0.68 grams nano-aluminum (40-70 nmdiameter; Argonide Nanomaterial Technologies, Sanford, Fla.), 1.23 gramsof nano-MoO₃ (EM-NTO-U2; Climax Molybdenum, Henderson, Colo.), and 0.2grams of nano-boron (33, 2445-25G; Aldrich). A slurry comprising theinitiator composition was prepared by adding 8.6 mL of 4.25% VITON® A500(4.25 grams VITON® in 100 mL amyl acetate (Mallinckrodt)) solution.

A 1.1 uL drop of slurry was deposited on the heating element, dried for20 minutes, and another 0.8 uL drop of slurry comprising the initiatorcomposition was deposited on the opposite side of the heating element.

Application of 3.0 V through a 1,000 μF capacitor from two A76 alkalinebatteries to the Nichrome heating element ignited the Al:MoO₃:Binitiator composition within 1 to 50 msec, typically within 1 to 6 msec.When positioned within 0.12″ inches of the surface of a solid fuelcomprising a metal reducing agent and a metal-containing oxidizing agentsuch as, for example, a fuel comprising 76.16% Zr:19.04% MoO₃:4.8%LAPONITE® RDS, the sparks produced by the initiator composition ignitedthe solid fuel to produce a self-sustaining exothermic reaction. Incertain embodiments, a 1 μL drop of the slurry comprising the initiatorcomposition can be deposited onto the surface of the solid fuel adjacentthe initiator composition disposed on the resistive heating element tofacilitate ignition of the solid fuel.

The initiator composition comprising Al:MoO₃:B adhered to the Nichromewire and maintained physical integrity following mechanical andenvironmental testing including temperature cycling (−25° C.

40° C.), drop testing, and impact testing.

In certain embodiments, as shown in FIG. 2D heating units can include athermal shunt 98, shown in FIG. 2D as a cylindrical rod disposed withinthe heating unit. In certain embodiments, the thermal shunt can beincorporated into the solid fuel expanse as a particulate, the thermalshunt can comprise the backing member and/or the thermal shunt can be aseparate element as shown. The thermal shunt can be in direct contactwith the solid fuel and/or can indirectly contact the solid fuel. Incertain embodiments, a thermal shunt can be capable of absorbing heatsuch that incorporation of a thermal shunt in a heating unit can controlor reduce the maximum temperature reached by the exterior surface of thesubstrate forming the heating unit. For example, in certain embodiments,the thermal shunt can comprise a material capable of undergoing a phasechange at or above the ignition temperature of the solid fuel. Examplesof phase change materials include low melting point metals such as tin,low melting point alloys such as Wood's metal and lead-tin alloys,inorganic salts, and mixtures thereof. In certain embodiments, thethermal shunt can comprise a material that can release absorbed heat toprolong the heating time of the heating unit. In certain embodiments, athermal shunt can comprise at least one material exhibiting a high heatcapacity, such as, for example, copper, aluminum, stainless steel andglass. Examples of materials that can release absorbed heat includesugars, waxes, metal salts and other materials capable of melting duringburning of the solid fuel and then undergoing crystallization as theheating unit cools, thus generating exothermic heat of crystallization,and mixtures thereof. Other materials capable of functioning as thermalshunts include porous and fibrous materials such as porous ceramicmembranes and/or fiber mats, and the like. Such materials can exhibit ahigh surface area that can facilitate heat transfer from the reactantsand reaction products to the material matrix. In certain embodiments,the porous and/or fibrous materials do not react with the reactants orreaction products produced during ignition and burn, and do not degradeand/or produce gaseous products at the temperatures achieved by theheating unit. In certain embodiments, the thermal shunt material cancomprise fibers including, but not limited to, metal fibers, silicafibers, glass fibers, graphite fibers, and/or polymer fibers.

In certain embodiments, the heating units described and illustrated inFIGS. 1A-1C and 2A-2D can be used in applications wherein rapid heatingis useful. In certain embodiments, a portion of the substrate can reacha maximum temperature in less than three seconds (3 sec), in certainembodiments less than 1 second (1 sec), in certain embodiments less than500 milliseconds, and in certain embodiments less than 250 milliseconds.

A heating unit substantially as illustrated in FIG. 2B was fabricated tomeasure the temperature of the exterior surface of the substratefollowing ignition of a solid fuel. Referring to FIG. 2B, cylindricalsubstrate 62 was approximately 1.5 inches in length and the diameter ofopen receptacle 66 was 0.6 inches. Solid fuel 80 comprising 75% Zr:25%MoO₃ in weight percent was placed in the inner region in the spacebetween the backing member 74 and the interior surface of substrate 62.A first initiator composition 82 comprising 5 mg of 10% Zr:22.5% B:67.5%KClO₃ in weight percent was placed in the depression of the retainingmember and 10 mg of a second initiator composition 94 of 10% Zr:22.5%B:67.5% KClO₃ in weight percent was placed in the open end 76 of backingmember 74 near the tapered portion of heating unit 60. Electrical leads88, 90 from two 1.5 V batteries provided a current of 0.3 Amps to ignitefirst initiator composition 82, thus producing sparks to ignite secondinitiator composition 94. Both initiators were ignited within 1 to 20milliseconds following application of the electrical current. Sparksproduced by second initiator composition 94 ignited solid fuel 80 in thetapered nose region 64 of the cylinder. Thermocouples placed on theexterior surface of substrate 62 were used to monitor the substratesurface temperature as a function of time. The exterior substratesurface reached a maximum temperature of 400° C. in less than 100milliseconds.

Upon ignition of the solid fuel, an exothermic oxidation-reductionreaction produces a considerable amount of energy in a short time, suchas for example, in certain embodiments less than 1 second, in certainembodiments less than 500 milliseconds, and in certain embodiments lessthan 250 milliseconds. Examples of exothermic reactions includeelectrochemical reactions and metal oxidation-reduction reactions. Whenused in enclosed heating units, by minimizing the quantity of reactantsand the reaction conditions the reaction can be controlled but canresult in a slow release of heat and/or a modest temperature rise.However, in certain applications, it can be useful to rapidly heat asubstrate to temperatures in excess of 200° C. within 1 second or less.Such rapid intense thermal pulses can be useful for vaporizingpharmaceutical compositions to produce aerosols. A rapid intense thermalpulse can be produced using an exothermic oxidation-reduction reactionand in particular a thermite reaction involving a metal and ametal-containing oxidizing agent. Concomitant with the rapid generationof heat, there can be a rapid generation of gaseous products andunreacted reactants with high translational energies. When sealed withinan enclosure, the exothermic oxidation-reduction reaction can generate asignificant increase in pressure.

Energy produced by the exothermic reaction, whether thermal, optical,mechanical, e.g. particle ejection, or chemical can generate asignificant pressure when contained with a sealed enclosure. In certainembodiments, a solid fuel capable of reacting in an exothermicoxidation-reduction reaction can be used to form a heating unit. Forexample, solid fuel as disclosed herein can be used to thermallyvaporize a drug coating to produce an aerosol of a drug for medicalapplications. In certain applications, such as in portable medicaldevices, it can be useful to contain the pyrothermic materials andproducts of the exothermic reaction and other chemical reactionsresulting from the high temperatures within the enclosure. Whilecontaining the exothermic reaction can be accomplished by adequatelysealing the enclosure to withstand the internal pressures resulting fromthe burning of the solid fuel as well as an initiator composition ifpresent, it can be useful to minimize the internal pressure to ensurethe safety of the heating device and facilitate device fabrication.

In certain embodiments, the pressure within the substrate can increaseduring and after ignition and burning of the initiator composition andthe solid fuel. The increase in pressure can depend, at least in part,on the amount and composition of the solid fuel, the relative amounts ofthe fuel components, the density and/or degree of compaction of thesolid fuel, the particle size of the fuel components, the configurationof the substrate, the amount of initiator, and/or the composition of theinitiator. In certain embodiments, a solid fuel, an initiatorcomposition, and a substrate configuration can be selected to controlthe pressure increase and maintain the maximum pressure within a usefuloperating range. The initiator composition and solid fuel can producegas phase reaction products during ignition and burn. Thus, in certainembodiments, the pressure within the substrate can be managed byminimizing the amount of initiator composition and solid fuel disposedwithin the heating unit. One of skill can experimentally determine theminimum amount of initiator composition needed to reliably ignite thesolid fuel. One of skill can also determine the properties,configuration, and placement of the solid fuel within a heating unit toachieve a useful substrate temperature.

In certain embodiments, the internal pressure of a heating unit can bemanaged or reduced by constructing the substrate, backing, and any otherinternal components from materials that produce minimal gas products atelevated temperatures. In certain embodiments, pressure can be managedor reduced by providing an interior volume wherein gas can be collectedand/or vented when the initiator and solid fuel are burned. In certainembodiments, the interior volume can include a porous or fibrousmaterial having a high surface area and a large interstitial volume. Theinterstitial volume can contain a gas generated as a result of theinitiator and solid fuel reactions and can thereby reduce the pressurewithin the enclosure and collisions of the reactants and reactionproducts with the matrix of the porous or fibrous material canefficiently transfer the internal and translational energy.

The internal pressure of a heating unit during and after burning of aninitiator composition and a solid fuel can vary depending on theparameters discussed above. The internal pressure of certain embodimentsof heating units was measured using the fixture illustrated in FIG. 3.As shown in FIG. 3, heating unit 300 comprises asubstantially-cylindrically shaped substrate 302 having a closed noseportion 304 and an open receiving end 306. A backing member 308 isdisposed within the interior region of substrate 302. Backing member 308is cylindrical in shape but of overall smaller dimensions than that ofsubstrate 302. Tapered nose portion 310 defines an opening 312 inbacking member 308. Opposing end 314 from tapered nose portion 310 ofbacking member 308 is open. The interior surface of substrate 302 andthe exterior surface of backing member 308 define an annular shell or agap into which a solid fuel 316 can be disposed. A plug 320 is sized forinsertion into open receiving end 306 of substrate 302 and is securelysealed by an O-ring 322. Electrodes 324 in contact with an initiatorcomposition (not shown) disposed within heating unit 300 extend throughplug 320 for electrical connection to a power source (not shown)external to heating unit 300. Pressure transducer 326 for measuring thesteady state pressure via line 328 within heating unit 300 can bemounted on plug 320. A dynamic pressure transducer 330 can be providedfor monitoring the pressure within heating unit 300 via line 332.

A heating unit equipped with two pressure transducers, as illustrated inFIG. 3, was used to simultaneously measure the dynamic pressure andsteady state pressure within a heating unit of a type as shown in FIG.2. For dynamic pressure measurement, a high frequency shock wave/blastICP pressure sensor (PCB, model 113A24, maximum pressure=1,000 psig)combined with a line powered ICP signal conditioner (PCB, model 484B06)was used. For steady state pressure measurement, a subminiaturemillivolt output type pressure transducer (Omega Engineering, modelPX600-500GV, maximum pressure=500 psig) and a high performance straingauge indicator with analog output (PCB, DP41-S-A) were used. Signalsgenerated by the pressure transducers were recorded and stored using twooscilloscopes. To minimize the influence of pressure measurement on theperformance of the heating unit, the volume of lines 328 and 332 weredesigned so as not to exceed 2% of the total unfilled internal volume ofthe heating unit. The measured internal pressure ranged from 100 psig to300 psig, and depended primarily on the composition of the solid fuel.The contribution of the initiator composition to the internal pressurewas a maximum 100 psig.

Measurements of the peak internal pressure within sealed heating units,of a type as shown in FIG. 10, following ignition of a thin film layerof solid fuel comprising a metal reducing agent and a metal-containingoxidizer are shown in FIG. 17. The experimental arrangement used togenerate the results shown in FIG. 17 is described in Example 2. FIG. 17shows that for certain embodiments, the peak pressure within a heatingunit can range from 10 psig to 40 psig and correlates with the peaktemperature of the exterior surface of the substrate. Also, as shown inFIG. 17, the peak pressure within the heating unit, as well as the peaktemperature of the substrate surface can for the particular embodimentsof heating units measure, depend on the composition of the solid fuel,and the thickness of the foil substrate.

The internal pressure within a heating unit can also be managed orreduced by incorporating materials capable of absorbing, adsorbing orreacting with gas phase reaction products. The surface of the materialmay intrinsically be capable of absorbing, adsorbing or reacting withthe gaseous products, or can be coated or decorated with, for example,elements, compounds and/or compositions. In certain embodiments, theimmediate burst of pressure resulting from the solid fuel burn can bereduced by locating an impulse absorbing material and/or coating withinthe heating unit. An embodiment of a heating unit comprising an impulseabsorbing material is schematically illustrated in FIG. 13.

FIGS. 13A-C show a thermally conductive substrate 210, such as metalfoil on which is disposed a coating of a solid fuel 212. Solid fuel 212can comprise a metal reducing agent and a metal-containing oxidizingagent capable of forming an oxidation-reduction reaction, such as, butnot limited to, any of those disclosed herein. In FIGS. 13A-C thermallyconductive substrate 210 is sealed using a sealant 220 to an enclosure218 to form the heating unit. Sealant 220 can be an adhesive or anyother methods for forming a seal, such as for example, welding,soldering, fastening or crimping. An impulse absorbing material 214 isdisposed between the interior surface of enclosure 218 and the interiorsurfaces of substrate 210 and the solid fuel 212. As shown in FIGS.13A-C, impulse absorbing material fills the interior volume defined bythe interior surfaces of the heating unit. In certain embodiments, theimpulse absorbing material can fill a portion of the interior volumedefined by the interior surfaces of the heating unit (not shown). Thethickness of the impulse absorbing material, e.g. the dimension betweenthe interior surface of solid fuel 212 and the interior surface ofenclosure 218 can be any appropriate thickness to reduce the initialpressure impulse resulting from the burning of solid fuel 212 to anappropriate level. The appropriate thickness can vary at least in parton the amount of solid fuel, the solid fuel composition, and/or thephysical characteristics of the impulse absorbing material such asporosity, density, and composition and the maximum acceptable pressurewithin the enclosure. It will be appreciated that above a certainthickness, additional impulse absorbing material can have limited effecton reducing the peak pressure within the heating unit. The impulseabsorbing material can comprise one or more materials and one or morelayers of impulse absorbing material. In certain embodiments whereinmultiple layers of impulse absorbing materials are used, each layer cancomprise the same or different material. In FIG. 13C, an element 216overlays impulse absorbing material 214. Element 216 can be the same ora different impulse absorbing material, and in certain embodiments, caninclude a getter. FIG. 13B illustrates a cross-sectional view of acylindrical heating unit comprising a substrate 210, a layer of solidfuel 212, and a central region filled with an impulse absorbing material214.

In certain embodiments, the impulse absorbing material can comprise amaterial which can absorb the thermal and translational energy of thereactants and reaction products produced during burning of the solidfuel, and if present, an initiator composition. In certain embodiments,an initiator composition comprising, for example, any of the initiatorcompositions disclosed herein, can be incorporated into the sealedheating unit to initiate the self-sustaining exothermic reaction of thesolid fuel. An impulse absorbing material can present a high surfacearea to absorb the pressure impulse of thermally and translationally hotmolecules and which does not react at the temperatures reached withinthe heating unit during and following the burn of the solid fuel.Examples of such materials include porous materials such as ceramicmembranes, and fibrous materials such as fiber mats. Hot moleculesphysically and/or thermally ejected from the burning solid fuel can passthrough the interstitial spaces defined by porous or fibrous matrix toaccess a large surface area, which upon collision, can facilitatetransfer of thermal and translational energy to the matrix of theimpulse absorbing material, thereby reducing the peak pressure withinthe heating unit.

Examples of porous membranes include, but are not limited to ceramicmembranes, fluorocarbon membranes, alumina membranes, polymer membranes,and membranes formed from sintered metal powders. Examples of fibrousmaterials include, but are not limited to, glass, silica, carbon,graphite, metals, and high temperature resistant polymers. Spongematerials can also be used. The porosity and density of the impulseabsorbing material can be selected to reduce the peak pressure by anappropriate amount. For a given amount of solid fuel, composition ofsolid fuel, and heating unit dimensions, the appropriate porosity anddensity of the impulse absorbing material can be determined empirically.In certain embodiments, it can be useful to have the pores sufficientlylarge to facilitate entry of the thermally and translationally hotmolecules to the interior of an impulse absorbing material, or to one ormore additional layers of impulse absorbing materials with differentporosity and/or composition to facilitate transfer of energy from thehot molecules to the impulse absorbing material.

The effect of incorporating glass fiber mats on the internal pressure ofa heating unit is shown in FIG. 14. Glass fiber mats were placed over acoating of solid fuel comprising an average mass of 177 mg of 80% Zr:20%MoO₃ disposed on a 0.004 inch thick stainless steel foil, and thepressure within the enclosure measured following ignition of the solidfuel. Each glass fiber mat was 0.040 inches thick. As shown in FIG. 14,glass fiber mats significantly reduced the peak internal pressure of theheating unit. When a single mat was used, the maximum pressure withinthe sealed enclosure was 22 psig, when two mats were used the maximumpressure was 13 psig, and when 5 mats were used, the peak pressure was 9psig.

The ability of glass fiber mats to reduce the temperature within aheating unit is shown in FIG. 15. The same experimental arrangement asdescribed for FIG. 14 was used. The peak temperature measured betweenthe solid fuel and the first mat was about 515° C. and 325° C., betweenthe first and second mats was about 200° C. and 180° C., and between thesecond and third mats was less than 100° C., thus demonstrating that theinternal and translational energy of the reactants and reaction productsis transferred to the impulse absorbing materials.

As demonstrated by the results shown in FIG. 14, the residual pressure,e.g. the pressure 10 seconds or more after solid fuel ignition, in theheating unit was insensitive to the presence of an impulse absorbingmaterial. Without being limited by theory, the residual pressure can bethe result of gases evolved and/or produced during the burning of thesolid fuel. Possible gas sources include hydrogen bonded to the metalreducing agent, and unreacted oxygen produced during the oxidationreaction and unreacted gaseous intermediates. For example, oxygengenerated by the metal-containing oxidizing agent may not immediatelyreact with the metal reducing agent, but rather can proceed throughseveral gaseous reaction intermediates.

In certain embodiments, the residual pressure within a heating unit canbe reduced by including materials capable of gettering the residualgaseous reaction products. Such materials can be included with theimpulse absorbing material, intrinsic to the impulse absorbing material,and/or applied to the impulse absorbing material as a coating, deposit,layer, and the like. In certain embodiments, the getter can be coated ordeposited onto a support disposed within a heating unit and/or on one ormore interior surfaces of the heating unit.

Getters are materials capable of absorbing, adsorbing and/or reactingwith gases and can be used to improve and/or maintain a vacuum, and/orto purify gases. Absorption refers to the process by which one materialis retained by another, such as the attachment of molecules of a gas orvapor to a solid surface by physical forces. Adsorption refers to theincrease in the concentration of a dissolved substance at the interfaceof a condensed and a gaseous or liquid phase. Getters are used forexample in the semiconductor industry to reduce residual gases in highvacuum systems. In certain embodiments, getters capable of removinghydrogen gas, H₂, and molecular oxygen, O₂, can include, but are notlimited to, compositions including metals and nonmetals, such as Ta, Zr,Tb, Ti, Al, Mg, Ba, Fe, and P. Examples of getters useful for removingH₂ gas include, but are not limited to, sintered Zr/graphite powders,Zr/Al compositions, Zr/V/Fe, polymer-bound getters such as PdO/zeolitedispersed in a polymer matrix, and polydiene hydrogenation catalystcompositions. Iron-based and polymeric getters have been developed toabsorb O₂. Carbon and/or graphite based materials can be used to adsorband/or absorb H₂ and O₂. In certain embodiments, a getter can alsoadsorb, absorb and/or react with volatile intermediate products or theunreacted reactants of the exothermic oxidation-reduction reaction suchas, for example, MoO_(x), CO, CO₂, and N₂.

A getter can be applied to a substrate by any appropriate method. Incertain embodiments, it can be useful to provide a large surface area ofgetter to rapidly and efficiently reduce the residual gas pressure. Thiscan be accomplished, for example, by providing a getter formed from aporous material, such as a sintered powder, or a fibrous material. Incertain embodiments, the getter can be applied to the surface of aporous or fibrous material.

Certain embodiments of heating units were used to examine the burnpropagation speed of the solid fuel following ignition. The burnpropagation speed refers to the speed of the burn front, which separatesunburned and burned solid fuel regions. In certain embodiments, the burnpropagation speed can be determined at least in part by the solid fuelcomposition, the particle size of the components of the solid fuel, thedensity or level of compaction of the solid fuel, the shape anddimensions of the solid fuel, the material forming the heating unit,and/or any internal components such as a backing member. The temporaland spatial characteristics of the burn propagation speed forcylindrically-shaped heating units were evaluated by monitoring thesurface temperature of heating units using an infrared thermal imagingcamera (FLIR Systems, Thermacam SC3000).

Thermal images of a cylindrically-shaped heating unit measured byinfrared thermal imaging as a function of time, in milliseconds, areshown in FIGS. 4A-4F. The construction of the heating unit used toproduce the thermal images is provided in Example 3. The substrate was1.5 cm in diameter and 4.5 cm in length. In FIGS. 4A-4F, two images areshown in each panel. In both images, white areas in color correspond toa surface temperature of 500° C. and black areas correspond to a surfacetemperature of 25° C. The top image corresponds to a front view of theheating unit and the lower image corresponds to a rear view of theheating unit, which was obtained from a reflection in a mirror mountedbehind the unit. FIG. 4A shows the extent of the self-propagating waveof ignited solid fuel 100 milliseconds after ignition. FIGS. 4B-4E,taken at 200, 300, 400, and 500 milliseconds after ignition,respectively, show that the wave of ignited fuel continued to propagatealong the axial direction of the heating unit. The image shown in FIG.4F was taken at 600 milliseconds after ignition, at which time theentire surface of the substrate was heated, indicating that the solidfuel was consumed. The data gathered from this and other studies usingvarious solid fuel compositions and heating unit configurationsdemonstrated that the burn propagation speed can range from 1.5 cm/secto 50 cm/sec. Thus, in certain embodiments, the speed at which heat istransferred to a substrate forming the heating unit can be tailored asuseful for certain applications.

In other studies, heating units as described in Examples 4A and 4B werefabricated and the surface temperature uniformity was evaluated byinfrared thermal imaging. Heating units prepared for these studiesdiffered from those used in the investigation of burn propagation speedonly in the mass ratio of metal and oxidizing agent used to form thesolid fuel. Thermal images taken 400 milliseconds after igniting thesolid fuel are shown in FIGS. 5A-5B. The image shown in FIG. 5Acorresponds to a heating unit comprising the solid fuel compositiondescribed in Example 4A and the image in FIG. 5B to a heating unitcomprising the solid fuel composition described in Example 4B. Thedimensions of the heated area were 1.5 cm by 4.5 cm. The exteriorsubstrate surface of the heating unit used to produce the image shown inFIG. 5B is more uniform than that of the heating unit shown in FIG. 5A.In certain embodiments, the substrate surface temperature can be moreuniform in heating units designed for axial flame propagation. Incertain embodiments, the substrate surface temperature is considereduniformly heated if no more than 10% of the exterior surface exhibits atemperature 50° C. to 100° C. less than the average temperature of theremaining 90% of the exterior surface.

In certain embodiments, it can be useful that at least a portion of theexterior surface of the substrate be heated to a uniform temperature,and that the heated portion be heated at a similar rate. Uniform heatingof at least a portion of the substrate can be facilitated by reducingthe thermal mass of the substrate in the region to be heated and/or bycontrolling the amount of solid fuel generating heat. Uniform heating ofthe exterior surface of the substrate can be useful for vaporizing acompound disposed on the exterior substrate surface in a short period oftime to form an aerosol comprising the vaporized compound having highyield and purity. As an example, uniform heating of a 1.3 inch by 1.3inch substrate area can be achieved by applying a 0.00163±0.000368 inchthick layer of solid fuel onto a 0.004 inch thick foil. Upon ignition,the surface of the foil opposing the surface on which 0.18 g of thesolid fuel is applied can reach a maximum temperature of 440° C. overthe 1.3 inch by 1.3 inch area at 250 msec after ignition. As will beappreciated by one of skill in the art, the fuel thickness selected willdepend on the fuel composition, the foil thickness, and the desiredtemperature.

Examples 5-7 provide heating units prepared and evaluated for pressureduring burn, burn propagation speed, and substrate temperatureuniformity. The heating unit described in Example 5 was comprised of asolid fuel composition of Zr, MoO₃, KClO₃, nitrocellulose, anddiatomaceous earth. After remote ignition of the solid fuel from the tipof the heating unit (opening 312 in FIG. 3), the internal pressureincreased to 150 psig during the burn period of 0.3 seconds. One minuteafter burn, the residual pressure was under 60 psig. The burnpropagation speed was measured by infrared thermal imaging to be 13cm/sec. With respect to surface temperature uniformity, no obvious coldspots were observed. (A cold spot, for purposes of Examples 5-7 herein,is defined as a portion of the surface exhibiting a temperature which is50° C. to 100° C. less than the average temperature of the remaining 90%of the exterior surface.)

The heating unit prepared as described in Example 6 contained a solidfuel composition comprised of Zr, MoO₃, and nitrocellulose. The gap orannular shell between the substrate and backing member was 0.020 inches.The external surface of the backing member was coated with initiatorcomposition to increase the burn propagation speed. The solid fuel wasremotely ignited from the tip of the heating unit (opening 312 in FIG.3). The internal pressure increased to 200 psig during the reactionperiod of 0.25 seconds, and the residual pressure was under 60 psig. Theburn propagation speed was 15 cm/sec. With respect to surfacetemperature uniformity, no obvious cold spots were observed.

The heating unit prepared as described in Example 7 contained a solidfuel composition of Al, MoO₃, and nitrocellulose. The solid fuel wasplaced in a 0.020-inch annular shell gap between the substrate and thebacking member. The solid fuel was directly ignited near the plug. Theinternal pressure increased to 300 psig during the reaction period ofless than 5 milliseconds. The residual pressure was under 60 psig. Theexterior surface of the substrate was uniformly heated, with between 5percent to 10 percent of the exterior surface exhibiting a temperature50° C. to 100° C. less than that of the remaining exterior surface.

Percussion Ignition

Percussion ignition can also be used to ignite the heating unit.Percussion ignition generally comprises a deformable ignition tubewithin which is an anvil coated with an initiator composition. Ignitionis activated by mechanical impact or force.

For the initiator composition to operate satisfactorily when actuated,the material must exhibit both the proper ignition sensitivity as wellas to ignite the solid fuel properly. Various initiator compositions canbe used but generally consists of a mixture of readily combustible fuelsuch as phosphorus with an oxidizer compound for the fuel such as alkalimetal chlorates and perchlorates. The initiator composition also furthergenerally includes a powdered combustible metal such as titanium,zirconium, hafnium, thorium, aluminum, magnesium, boron, silicon ortheir alloys. Typically, the initiator compositions are prepared asliquid suspension in an organic or aqueous solvent for easy handling andcoating the anvil and soluble binders are generally included to provideadhesion of the coating to the anvil if required.

The initiator composition can be mixed using conventional methods toprovide an even blend of the constituents. Typically, all solidmaterials can have a particle range from a fine mesh size to a micronsize or a nanometer size. By changing the ratio of the solid materialsin the initiator composition, it is possible to make the final initiatorcomposition release more or less energy, as is needed, and to be more orless sensitive to light pulses, air or oxygen and shock.

The coating of the initiator material can be applied to the anvil invarious known ways. For example, the anvil can be dipped into a slurryof the initiator composition followed by drying in air or heat to removethe liquid and produce a solid adhered coating have the desiredcharacteristic previously described. Alternately, the slurry can besprayed or spin coated on the anvil and thereafter processed to providea solid coating. The thickness of the coating of the initiatorcomposition on the anvil should be such, that when the anvil is place inthe ignition tube, the initiator composition is a slight distance ofaround a few thousandths of an inch or so, for example, 0.004 inch, forthe inside wall of the ignition tube.

The anvil on which the initiator composition is disposed is typically ametal wire or rod. It should be of a suitable metallic composition suchthat it exhibits a high temperature resistance and low thermalconductivity, such as, for example, stainless steel. The anvil isdisposed within the metal ignition tube and extended substantiallycoaxially. Thus, the anvil should be of a slightly smaller diameter thanthe inside diameter of the ignition tube so as to be spaced a slightdistance, for example, about 0.05 inch or so from the inside wallthereof.

The anvil is disposed within a metal ignition tube. The ignition tubeshould be of readily deformable materials and can comprise a thin-walled(for example, 0.003-inch wall thickness) tube of a suitable metalliccomposition, such as for example, aluminum, nickel-chromium iron alloy,brass, or steel. The anvil can be held or fastened in place in theignition tube near its outer tube by crimping or any other methodtypically used.

Ignition of the fuel is actuated by a forceful mechanical impact or blowapplied against the side of the metal ignition tube to deform itinwardly against the coating of the initiator material on the anvil,which causes deflagration of the initiator material up through theignition tube into the fuel coated heating unit. Various means forproviding mechanic impact can be used. In certain embodiments a springloaded impinger or striker is used to actuate the ignition.

An embodiment of a heating unit 800 comprising a percussive igniter isillustrated in FIG. 21. As shown in FIG. 21, a deformable ignition tube805, with an initiator composition coated anvil 803 contained therein,is placed between two substrates 801 coated with solid fuel 802, withthe open end of the ignition tube disposed within the heating unit 800.The heating unit 800 is then sealed

An example of the preparation of a heating unit using percussionignition is described in Example 11. The advantages of such an ignitionsystem over resistive ignition are that it eliminates the need for useof battery and is a very cost effective means of ignition.

Optical Ignition

Optical ignition can also be used to ignite the heating unit. Opticalignition requires the use either a light sensitive material or initiatorcomposition and a light source for actuation of the light sensitivematerial or initiator composition or a very high intensity light source,e.g., a laser.

Various light sensitive initiator compositions can be used, but theygenerally consist of combustible materials that are light absorptive orare coated with light absorptive chemicals. Black powder andnitrocellulose powders are sufficiently light absorptive without anycoatings. Metal and oxidizing agent compositions, such as thosediscussed above, can also be used. In certain embodiments, metals suchas, for example, aluminum, zirconium, and titanium and oxidizing agentssuch as potassium chlorate, potassium perchlorate, copper oxide,tungsten trioxide, and molybdenum trioxide can be used. Initiatorcompositions that are sensitive to a specific wavelength or range ofwavelengths, such as, for example, compositions that are highlyabsorptive in the ultraviolet region of the electromagnetic spectrum canalso be used.

The initiator material can be applied directly to the fuel on thesubstrate or positioned elsewhere within the heating unit. In certainembodiments, initiator compositions can be within a hole in glass fiberfilter that is placed adjacent to the surface of the coated fuel.

Ignition of the fuel in a heat package is actuated by transmission of alight pulse through a clear optical window to the initiatorcompositions. The optical window can be made of any material thatreadily transmits a light pulse, such as for example, glass, acrylic, orpolycarbonate. The window can be positioned in any location to transmitthe light to the initiator. In certain embodiments, the window formspart of the enclosure of the heating unit. In other embodiments, thewindow is completely contained in the system. In certain embodiments thewindow is part of a light guide assembly. The light guide assembly canalso consist of a beam splitter. The light coming from the light sourcepasses through the beam splitter and can directed to two or moreinitiator compositions located within the heating unit for initiation oftwo or more fuel coated substrates at the same time or in sequence.Optionally, an optical fiber can be used to fire multiple heating unitsat the same time. In other embodiments, the window can be coated by amaterial which causes the wavelength of the light which it emits to bedifferent from the light which it receives. For example, the radiantoptical source could emit ultraviolet light, and the coating could beused to give off a visible wavelength in response to the ultravioletlight.

Various means for actuating the optical ignition can be used. In certainembodiments, an electrically conductive means for generating a lightpulse upon achieving a threshold voltage is provided. The electricallyconductive means can be part of the heating unit itself, e.g., includedin a spacer of the heating unit or separate from the heating unit. Theelectrically conductive means for generating a light pulse can include,for example a Xenon flash lamp, a light emitting diode, and a laser.

Several embodiments of a heating unit 900 comprising an optical ignitionsystem are illustrated in FIGS. 20A-D. As shown in 20A-D, an initiatorcomposition 904 is contained within a hole 908 in an impulse absorbingmaterial 903, such that the initiator composition 904 is adjacent to thefuel coating. One or more an impulse absorbing materials 903 can beadded to the heating unit, as long as there is not an obstruction by theimpulse absorbing material that would prevent contact between theignited initiator composition and the solid fuel. Holes or spaces 908can be cut into the impulse absorbing materials 903 to provide anopening for such contact, as is demonstrated in FIGS. 20A-B. More thanone initiator composition 904 can be placed in a single heating unit900, as shown in FIGS. 20B and D, for initiating the firing of more thanone solid fuel coating at a time. Additionally, a single initiatorcomposition 904 can be placed in each impulse absorbing material 903, toform several heating units combined in one device 910, such asdemonstrated in FIG. 20C. The impulse absorbing material can be fit intoa spacer 902 as shown in FIGS. 20A-B, and Fig. D, or into a cavity 909generated in multiply layers of a sealant 906, as shown in FIG. 20C.

As shown in FIG. 20A and FIG. 20C, an optical window 901 can form partof the enclosure of the heating unit. In some embodiments, the opticalwindow 901 forms part of a wave guide system (not shown) which includesa beam splitter 907, as shown in FIG. 20B. The beam splitter 907 can beused to direct one source of light to two initiator compositions so asto ignite both solid fuel coated substrates 905 together.

Various means can be used to seal the heating unit. Sealant 906 can bean adhesive, such as double sided tape or epoxy, or any other methodsfor forming a seal, such as for example, welding, soldering, fasteningor crimping.

In certain embodiments, the light source 911 is part of the heatingunit, and can be contained within the spacer 902 contained in theheating unit 900, as shown in FIG. 20D. The light source can be poweredby a battery (not shown).

An example of the preparation of a single heating unit using opticalignition is described in Example 11. Example 12 describes thepreparation of a device with multiple optically ignitable heating units.One advantage of such an ignition system is that there is no need for adirect electrical connection between a battery and the initiatorcomposition, as is required for electrical resistive heating.Additionally, the initiator composition can be ignited within theheating unit without the need for a bridgewire.

Drug Supply Unit

Certain embodiments include a drug supply unit comprising a heating unitas described herein. A drug supply unit can be used in a drug deliverydevice where a drug is to be thermally vaporized and then condensed foradministration to a user. In certain embodiments, the drug condensatecan be administered by inhalation, nasal ingestion, or topically. Drugrefers to any compound for therapeutic use or non-therapeutic use,including therapeutic agents and substances. Therapeutic agent refers toany compound for use in the diagnosis, cure, mitigation, treatment, orprevention of disease, and any compound used in the mitigation ortreatment of symptoms of disease. Whereas, substances refer to compoundsused for a non-therapeutic use, typically for a recreational orexperimental purpose.

FIGS. 6A-6C schematically illustrate cross-sectional views of a drugsupply unit 100 comprising a heating unit similar to that described inFIG. 2B. More specifically, FIGS. 6A-6C illustrate a drug supply unit100 having a film of drug disposed on the exterior substrate surface(FIG. 6A); ignition of the heating unit (FIG. 6B); and generation of awave of heat effective to vaporize the drug film (FIG. 6C). With initialreference to FIG. 6A, drug supply unit 100 comprises a heating unit 102,similar to that described in FIG. 2B. In FIGS. 6A-B, a substantiallycylindrically-shaped, heat-conductive substrate 104 has an exteriorsurface 106 and an interior surface 108, which define an inner region112. A film 110 of drug can be disposed on all or a portion of exteriorsurface 106.

In certain embodiments, film 110 can be applied to exterior substratesurface 106 by any appropriate method and can depend at least in part onthe physical properties of the drug and the final thickness of the film.In certain embodiments, methods of applying a drug to the exteriorsubstrate surface include, but are not limited to, brushing, dipcoating, spray coating, screen printing, roller coating, inkjetprinting, vapor-phase deposition, spin coating, and the like. In certainembodiments, the drug can be prepared as a solution comprising at leastone solvent and applied to the exterior surface. In certain embodiments,a solvent can comprise a volatile solvent such as, for example, but notlimitation, acetone or isopropanol. In certain embodiments, the drug canbe applied to the exterior surface of the substrate as a melt. Incertain embodiments, the drug can be applied to a support having arelease coating and transferred to a substrate from the support. Fordrugs that are liquid at room temperature, thickening agents can beadmixed with the drug to produce a viscous composition comprising thedrug that can be applied to the exterior substrate surface by anyappropriate method, including those described herein. In certainembodiments, a film of compound can be formed during a singleapplication or can be formed during repeated applications to increasethe final thickness of the film. In certain embodiments, the finalthickness of a film of drug disposed on the exterior substrate surfacecan be less than 50 μm, in certain embodiments less than 20 μm and incertain embodiments less than 10 μm, in certain embodiments the filmthickness can range from 0.02 μm to 20 μm, and in certain embodimentscan range from 0.1 μm to 10 μm.

In certain embodiments, the film can comprise a therapeuticallyeffective amount of at least one drug. Therapeutically effective amountrefers to an amount sufficient to affect treatment when administered toa patient or user in need of treatment. Treating or treatment of anydisease, condition, or disorder refers to arresting or ameliorating adisease, condition or disorder, reducing the risk of acquiring adisease, condition or disorder, reducing the development of a disease,condition or disorder or at least one of the clinical symptoms of thedisease, condition or disorder, or reducing the risk of developing adisease, condition or disorder or at least one of the clinical symptomsof a disease or disorder. Treating or treatment also refers toinhibiting the disease, condition or disorder, either physically, e.g.stabilization of a discernible symptom, physiologically, e.g.,stabilization of a physical parameter, or both, and inhibiting at leastone physical parameter that may not be discernible to the patient.Further, treating or treatment refers to delaying the onset of thedisease, condition or disorder or at least symptoms thereof in a patientwhich may be exposed to or predisposed to a disease, condition ordisorder even though that patient does not yet experience or displaysymptoms of the disease, condition or disorder. In certain embodiments,the drug film can comprise one or more pharmaceutically acceptablecarriers, adjuvants, and/or excipients. Pharmaceutically acceptablerefers to approved or approvable by a regulatory agency of the Federalor a state government or listed in the U.S. Pharmacopoeia or othergenerally recognized pharmacopoeia for use in animals, and moreparticularly in humans.

As shown in FIGS. 6A-6C, substrate 104 of drug supply unit 100 candefine an inner region 112 in which a solid fuel 114 can be disposed. Asshown, solid fuel 114 can be disposed as an annular shell defined byinterior substrate surface 108 and an inner, cylindrical backing member118. A first initiator composition 120 can be located at one end ofcylindrical backing member 118 and a second initiator composition 122can be located at the opposing end of cylindrical backing member 118.First initiator composition 120 can be in physical contact with anelectrically resistive heating element via electrical leads 124, 126 toa power source (not shown).

As shown in FIG. 6B, application of an electrical current provided by apower source (not shown) to leads 124, 126 can cause initiatorcomposition 120 to produce sparks, such as sparks 128, 130 that can bedirected toward second initiator composition 122. Ignition of secondinitiator composition 122 can ignite solid fuel 114 in the regionindicated by mows 132, 134. Igniting solid fuel 114 in the regionindicated by arrows 132, 134 effectuates a self-propagating wave ofburning solid fuel, as schematically illustrated in FIG. 6C. In FIG. 6C,the self-propagating burn is indicated by arrows 136, 138, 140, 142 withthe solid fuel burn propagating from the point of ignition through thesolid fuel. As the solid fuel burns, heat can be produced that can beconducted through substrate 104 causing vaporization of drug film 110disposed on external substrate surface 106. In FIG. 6C, thermallyvaporized drug is illustrated as the “cloud” of drug 144. In certainembodiments, as illustrated in FIG. 6C, vaporization of the drug occursin the direction of arrows 136, 138, 140, 142, where the film nearestthe ignition point of the solid fuel is vaporized first, followed byvaporization in regions along the length of drug supply unit 100. Asshown in FIG. 6C, thermally vaporized drug 144 is illustrated at thetapered region of drug supply unit 100, and drug film not yet vaporizedfrom the exterior surface 106 is illustrated at point 110.

FIGS. 7A-7E represent high-speed photographs showing the thermalgeneration of a vapor from a drug supply unit similar to that describedin FIGS. 6A-6C. FIG. 7A shows a heat-conductive substrate 4 cm in lengthcoated with a 3 μm to 5 μm thick film of the therapeutic agentalprazolam. The drug-coated substrate was placed in a chamber throughwhich a stream of air was flowing in an upstream-to-downstreamdirection, indicated by the arrow in FIG. 7A, at a rate of 15 L/minSolid fuel contained in the heating unit was ignited to heat thesubstrate. The progression of drug vaporization from the exteriorsurface of the drug supply unit was monitored using real-timephotography. FIGS. 7B-7E show the sequence of thermal vaporization attime intervals of 150 msec, 250 msec, 500 msec, and 1,000 msec,following ignition of an initiator composition, respectively. The cloudof thermal vapor formed from the drug film is visible in thephotographs. Complete vaporization of the drug film was achieved in lessthan 1,000 msec.

The drug supply unit is configured such that the solid fuel heats aportion of the exterior surface of the substrate to a temperaturesufficient to thermally vaporize the drug in certain embodiments withinat least 3 seconds following ignition of the solid fuel, in otherembodiments within 1 second following ignition of the solid fuel, inother embodiments within 800 milliseconds following ignition of thesolid fuel, in other embodiments within 500 milliseconds followingignition of the solid fuel, and in other embodiments within 250milliseconds following ignition of the solid fuel.

In certain embodiments, a drug supply unit can generate an aerosolcomprising a drug that can be inhaled directly by a user and/or can bemixed with a delivery vehicle, such as a gas, to produce a stream fordelivery, e.g., via a spray nozzle, to a topical site for a variety oftreatment regimens, including acute or chronic treatment of a skincondition, administration of a drug to an incision site during surgery,or to an open wound.

In certain embodiments, rapid vaporization of a drug film can occur withminimal thermal decomposition of the drug. For example, in certainembodiments, less than 10% of the drug is decomposed during thermalvaporization, and in certain embodiments, less than 5% of the drug isdecomposed during thermal vaporization. In certain embodiments, a drugcan undergo a phase transition to a liquid state and then to a gaseousstate, or can sublime, i.e., pass directly from a solid state to agaseous state. In certain embodiments, a drug can include apharmaceutical compound. In certain embodiments, the drug can comprise atherapeutic compound or a non-therapeutic compound. A non-therapeuticcompound refers to a compound that can be used for recreational,experimental, or pre-clinical purposes. Classes of drugs that can beused include, but are not limited to, anesthetics, anticonvulsants,antidepressants, antidiabetic agents, antidotes, antiemetics,antihistamines, anti-infective agents, antineoplastics, antiparkisoniandrugs, antirheumatic agents, antipsychotics, anxiolytics, appetitestimulants and suppressants, blood modifiers, cardiovascular agents,central nervous system stimulants, drugs for Alzheimer's diseasemanagement, drugs for cystic fibrosis management, diagnostics, dietarysupplements, drugs for erectile dysfunction, gastrointestinal agents,hormones, drugs for the treatment of alcoholism, drugs for the treatmentof addiction, immunosuppressives, mast cell stabilizers, migrainepreparations, motion sickness products, drugs for multiple sclerosismanagement, muscle relaxants, nonsteroidal anti-inflammatories, opioids,other analgesics and stimulants, opthalmic preparations, osteoporosispreparations, prostaglandins, respiratory agents, sedatives andhypnotics, skin and mucous membrane agents, smoking cessation aids,Tourette's syndrome agents, urinary tract agents, and vertigo agents.

Examples of anesthetic include ketamine and lidocaine.

Examples of anticonvulsants include compounds from one of the followingclasses: GABA analogs, tiagabine, vigabatrin; barbiturates such aspentobarbital; benzodiazepines such as clonazepam; hydantoins such asphenyloin; phenyltriazines such as lamotrigine; miscellaneousanticonvulsants such as carbamazepine, topiramate, valproic acid, andzonisamide.

Examples of antidepressants include amitriptyline, amoxapine, benmoxine,butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine,kitanserin, lofepramine, medifoxamine, mianserin, maprotoline,mirtazapine, nortriptyline, protriptyline, trimipramine, venlafaxine,viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine,milnacipran, nisoxetine, paroxetine, reboxetine, sertraline, tianeptine,acetaphenazine, binedaline, brofaromine, cericlamine, clovoxamine,iproniazid, isocarboxazid, moclobemide, phenyhydrazine, phenelzine,selegiline, sibutramine, tranylcypromine, ademetionine, adrafinil,amesergide, amisulpride, amperozide, benactyzine, bupropion, caroxazone,gepirone, idazoxan, metralindole, milnacipran, minaprine, nefazodone,nomifensine, ritanserin, roxindole, S-adenosylmethionine, escitalopram,tofenacin, trazodone, tryptophan, and zalospirone.

Examples of antidiabetic agents include pioglitazone, rosiglitazone, andtroglitazone.

Examples of antidotes include edrophonium chloride, flumazenil,deferoxamine, nalmefene, naloxone, and naltrexone.

Examples of antiemetics include alizapride, azasetron, benzquinamide,bromopride, buclizine, chlorpromazine, cinnarizine, clebopride,cyclizine, diphenhydramine, diphenidol, dolasetron, droperidol,granisetron, hyoscine, lorazepam, dronabinol, metoclopramide,metopimazine, ondansetron, perphenazine, promethazine, prochlorperazine,scopolamine, triethylperazine, trifluoperazine, triflupromazine,trimethobenzamide, tropisetron, domperidone, and palonosetron.

Examples of antihistamines include astemizole, azatadine,brompheniramine, carbinoxamine, cetrizine, chlorpheniramine,cinnarizine, clemastine, cyproheptadine, dexmedetomidine,diphenhydramine, doxylamine, fexofenadine, hydroxyzine, loratidine,promethazine, pyrilamine and terfenidine.

Examples of anti-infective agent include compounds selected from one ofthe following classes: antivirals such as efavirenz; AIDS adjunct agentssuch as dapsone; aminoglycosides such as tobramycin; antifungals such asfluconazole; antimalarial agents such as quinine; antituberculosisagents such as ethambutol; β-lactams such as cefmetazole, cefazolin,cephalexin, cefoperazone, cefoxitin, cephacetrile, cephaloglycin,cephaloridine; cephalosporins, such as cephalosporin C, cephalothin;cephamycins such as cephamycin A, cephamycin B, and cephamycin C,cephapirin, cephradine; leprostatics such as clofazimine; penicillinssuch as ampicillin, amoxicillin, hetacillin, carfecillin, carindacillin,carbenicillin, amylpenicillin, azidocillin, benzylpenicillin,clometocillin, cloxacillin, cyclacillin, methicillin, nafcillin,2-pentenylpenicillin, penicillin N, penicillin O, penicillin S,penicillin V, dicloxacillin; diphenicillin; heptylpenicillin; andmetampicillin; quinolones such as ciprofloxacin, clinafloxacin,difloxacin, grepafloxacin, norfloxacin, ofloxacine, temafloxacin;tetracyclines such as doxycycline and oxytetracycline; miscellaneousanti-infectives such as linezolide, trimethoprim and sulfamethoxazole.

Examples of anti-neoplastic agents include droloxifene, tamoxifen, andtoremifene.

Examples of antiparkisonian drugs include amantadine, baclofen,biperiden, benztropine, orphenadrine, procyclidine, trihexyphenidyl,levodopa, carbidopa, andropinirole, apomorphine, benserazide,bromocriptine, budipine, cabergoline, eliprodil, eptastigmine, ergoline,galanthamine, lazabemide, lisuride, mazindol, memantine, mofegiline,pergolide, piribedil, pramipexole, propentofylline, rasagiline,remacemide, ropinerole, selegiline, spheramine, terguride, entacapone,and tolcapone.

Examples of antirheumatic agents include diclofenac, hydroxychloroquineand methotrexate.

Examples of antipsychotics include acetophenazine, alizapride,amisulpride, amoxapine, amperozide, aripiprazole, benperidol,benzquinamide, bromperidol, buramate, butaclamol, butaperazine,carphenazine, carpipramine, chlorpromazine, chlorprothixene,clocapramine, clomacran, clopenthixol, clospirazine, clothiapine,clozapine, cyamemazine, droperidol, flupenthixol, fluphenazine,fluspirilene, haloperidol, loxapine, melperone, mesoridazine,metofenazate, molindrone, olanzapine, penfluridol, pericyazine,perphenazine, pimozide, pipamerone, piperacetazine, pipotiazine,prochlorperazine, promazine, quetiapine, remoxipride, risperidone,sertindole, spiperone, sulpiride, thioridazine, thiothixene,trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepine,and zuclopenthixol.

Examples of anxiolytics include alprazolam, bromazepam, oxazepam,buspirone, hydroxyzine, mecloqualone, medetomidine, metomidate,adinazolam, chlordiazepoxide, clobenzepam, flurazepam, lorazepam,loprazolam, midazolam, alpidem, alseroxlon, amphenidone, azacyclonol,bromisovalum, captodiamine, capuride, carbcloral, carbromal, chloralbetaine, enciprazine, flesinoxan, ipsapiraone, lesopitron, loxapine,methaqualone, methprylon, propanolol, tandospirone, trazadone,zopiclone, and zolpidem.

An example of an appetite stimulant is dronabinol.

Examples of appetite suppressants include fenfluramine, phentermine andsibutramine.

Examples of blood modifiers include cilostazol and dipyridamol.

Examples of cardiovascular agents include benazepril, captopril,enalapril, quinapril, ramipril, doxazosin, prazosin, clonidine,labetolol, candesartan, irbesartan, losartan, telmisartan, valsartan,disopyramide, flecanide, mexiletine, procainamide, propafenone,quinidine, tocamide, amiodarone, dofetilide, ibutilide, adenosine,gemfibrozil, lovastatin, acebutalol, atenolol, bisoprolol, esmolol,metoprolol, nadolol, pindolol, propranolol, sotalol, diltiazem,nifedipine, verapamil, spironolactone, bumetanide, ethacrynic acid,furosemide, torsemide, amiloride, triamterene, and metolazone.

Examples of central nervous system stimulants include amphetamine,brucine, caffeine, dexfenfluramine, dextroamphetamine, ephedrine,fenfluramine, mazindol, methyphenidate, pemoline, phentermine,sibutramine, and modafinil.

Examples of drugs for Alzheimer's disease management include donepezil,galanthamine and tacrin.

Examples of drugs for cystic fibrosis management include CPX, IBMX, XACand analogues; 4-phenylbutyric acid; genistein and analogousisoflavones; and milrinone.

Examples of diagnostic agents include adenosine and aminohippuric acid.

Examples of dietary supplements include melatonin and vitamin-E.

Examples of drugs for erectile dysfunction include tadalafil,sildenafil, vardenafil, apomorphine, apomorphine diacetate,phentolamine, and yohimbine.

Examples of gastrointestinal agents include loperamide, atropine,hyoscyamine, famotidine, lansoprazole, omeprazole, and rebeprazole.

Examples of hormones include: testosterone, estradiol, and cortisone.

Examples of drugs for the treatment of alcoholism include naloxone,naltrexone, and disulfuram.

Examples of drugs for the treatment of addiction it is buprenorphine.

Examples of immunosupressives include mycophenolic acid, cyclosporin,azathioprine, tacrolimus, and rapamycin.

Examples of mast cell stabilizers include cromolyn, pemirolast, andnedocromil.

Examples of drugs for migraine headache include almotriptan,alperopride, codeine, dihydroergotamine, ergotamine, eletriptan,frovatriptan, isometheptene, lidocaine, lisuride, metoclopramide,naratriptan, oxycodone, propoxyphene, rizatriptan, sumatriptan,tolfenamic acid, zolmitriptan, amitriptyline, atenolol, clonidine,cyproheptadine, diltiazem, doxepin, fluoxetine, lisinopril,methysergide, metoprolol, nadolol, nortriptyline, paroxetine, pizotifen,pizotyline, propanolol, protriptyline, sertraline, timolol, andverapamil.

Examples of motion sickness products include diphenhydramine,promethazine, and scopolamine.

Examples of drugs for multiple sclerosis management include bencyclane,methylprednisolone, mitoxantrone, and prednisolone.

Examples of muscle relaxants include baclofen, chlorzoxazone,cyclobenzaprine, methocarbamol, orphenadrine, quinine, and tizanidine.

Examples of nonsteroidal anti-inflammatory drugs include aceclofenac,acetaminophen, alminoprofen, amfenac, aminopropylon, amixetrine,aspirin, benoxaprofen, bromfenac, bufexamac, carprofen, celecoxib,choline, salicylate, cinchophen, cinmetacin, clopriac, clometacin,diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen,indomethacin, indoprofen, ketoprofen, ketorolac, mazipredone,meclofenamate, nabumetone, naproxen, parecoxib, piroxicam, pirprofen,rofecoxib, sulindac, tolfenamate, tolmetin, and valdecoxib.

Examples of opioid drugs include alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,carbiphene, cipramadol, clonitazene, codeine, dextromoramide,dextropropoxyphene, diamorphine, dihydrocodeine, diphenoxylate,dipipanone, fentanyl, hydromorphone, L-alpha acetyl methadol,lofentanil, levorphanol, meperidine, methadone, meptazinol, metopon,morphine, nalbuphine, nalorphine, oxycodone, papaveretum, pethidine,pentazocine, phenazocine, remifentanil, sufentanil, and tramadol.

Examples of other analgesic drugs include apazone, benzpiperylon,benzydramine, caffeine, clonixin, ethoheptazine, flupirtine, nefopam,orphenadrine, propacetamol, and propoxyphene.

Examples of opthalmic preparation drugs include ketotifen and betaxolol.

Examples of osteoporosis preparation drugs alendronate, estradiol,estropitate, risedronate and raloxifene.

Examples of prostaglandin drugs include epoprostanol, dinoprostone,misoprostol, and alprostadil.

Examples of respiratory agents include albuterol, ephedrine,epinephrine, fomoterol, metaproterenol, terbutaline, budesonide,ciclesonide, dexamethasone, flunisolide, fluticasone propionate,triamcinolone acetonide, ipratropium bromide, pseudoephedrine,theophylline, montelukast, zafirlukast, ambrisentan, bosentan,enrasentan, sitaxsentan, tezosentan, iloprost, treprostinil, andpirfenidone

Examples of sedative and hypnotic drugs include butalbital,chlordiazepoxide, diazepam, estazolam, flunitrazepam, flurazepam,lorazepam, midazolam, temazepam, triazolam, zaleplon, zolpidem, andzopiclone.

Examples of skin and mucous membrane agents include isotretinoin,bergapten and methoxsalen.

Examples of smoking cessation aids include nicotine and varenicline.

An example of a Tourette's syndrome agent includes pimozide.

Examples of urinary tract agents include tolteridine, darifenicin,propantheline bromide, and oxybutynin.

Examples of vertigo agents include betahistine and meclizine.

In certain embodiments, a drug can further comprise substances toenhance, modulate and/or control release, aerosol formation,intrapulmonary delivery, therapeutic efficacy, therapeutic potency,stability, and the like. For example, to enhance therapeutic efficacy adrug can be co-administered with one or more active agents to increasethe absorption or diffusion of the first drug through the pulmonaryalveoli, or to inhibit degradation of the drug in the systemiccirculation. In certain embodiments, a drug can be co-administered withactive agents having pharmacological effects that enhance thetherapeutic efficacy of the drug. In certain embodiments, a drug cancomprise compounds that can be used in the treatment of one or morediseases, conditions, or disorders. In certain embodiments, a drug cancomprise more than one compound for treating one disease, condition, ordisorder, or for treating more than one disease, condition, or disorder.

Thin Film Drug Supply Unit

An embodiment of a thin film drug supply unit is illustrated in FIGS.10A-10B. FIG. 10A illustrates a perspective view, and FIG. 10B anassembly view of a thin film drug supply unit 500. Thin film drug supplyunit 500 comprises, as shown in FIG. 10B, a thin film heating unit 530on which is disposed a drug 514 to be thermally vaporized. As shown inFIG. 10A, thin film heating unit 530 comprises a first and a secondsubstrate 510, and a spacer 518.

As shown, first and second substrates 510 include an area comprisingsolid fuel 512 disposed on the interior surface, and an area comprisinga drug 514 to be vaporized disposed on the exterior surface. First andsecond substrates 510 can comprise a thermally conductive material suchas those described herein, including, for example, metals, ceramics, andthermally conductive polymers. In certain embodiments, substrates 510can comprise a metal, such as, but not limited to, stainless steel,copper, aluminum, and nickel, or an alloy thereof. Substrates can haveone or more layers, and the multiple layers can comprise differentmaterials. For example, a substrate can comprise multiple layers oflaminated metal foils, and/or can comprise thin films of one or morematerials deposited on the surface. The multiple layers can be used forexample to determine the thermal properties of the substrate and/or canbe used to determine the reactivity of the surface with respect to acompound disposed on the exterior surface. A multilayer substrate canhave regions comprising different materials. The thickness of substrates510 can be thin to facilitate heat transfer from the interior to theexterior surface and/or to minimize the thermal mass of the device. Incertain embodiments, a thin substrate can facilitate rapid andhomogeneous heating of the exterior surface with a lesser amount ofsolid fuel compared to a thicker substrate. Substrate 510 can alsoprovide structural support for solid fuel 512 and drug film 514. Incertain embodiments, substrates 510 can comprise a metal foil. Incertain embodiments, the thickness of substrates 510 can range from0.001 inches to 0.020 inches, in certain embodiments from 0.001 inchesto 0.010 inches, in certain embodiments from 0.002 inches to 0.006inches, and in certain embodiments from 0.002 inches to 0.005 inches.The use of lesser amounts of solid fuel can facilitate control of theheating process as well as facilitate miniaturization of a drug supplyunit.

In certain embodiments, the thickness of substrates 510 can vary acrossthe surface. For example, a variable thickness can be useful forcontrolling the temporal and spatial characteristics of heat transferand/or to facilitate sealing of the edges of substrates 510, forexample, to spacer 518, opposing substrate 510, or to another support(not shown). In certain embodiments, substrates 510 can exhibit ahomogeneous or nearly homogeneous thickness in the region of thesubstrate on which solid fuel 512 and drug 514 are disposed tofacilitate achieving a homogeneous temperature across that region of thesubstrate on which the solid fuel is disposed. Homogeneous heating ofthe substrate can facilitate the production of an aerosol comprising ahigh purity of a drug or pharmaceutical composition and maximize theyield of drug initially deposited on the substrate forming an aerosol.

Substrates 510 can comprise an area of solid fuel 512 disposed on theinterior surface, e.g. the surface facing opposing substrate 510. Anappropriate amount of solid fuel 512 can in part be determined by thethermal vaporization or sublimation temperature of the drug, the amountof drug to be vaporized, the thickness and thermal conductivity of thesubstrate, the composition of the solid fuel, and the temporalcharacteristics of the intended thermal vaporization process. Solid fuel512 can be applied to substrate 510 using any appropriate method. Forexample, solid fuel 512 can be applied to substrate 510 by brushing, dipcoating, screen printing, roller coating, spray coating, inkjetprinting, stamping, spin coating, and the like. To facilitateprocessing, solid fuel 510 can comprise at least one additive material,and/or a solvent, as disclosed herein. In certain embodiments, solidfuel 512 can be formed as a preformed sheet that can be cut to aspecific dimension and subsequently applied to substrate 510. In certainembodiments, the solid fuel can be applied to a support, and transferredto a substrate as a preformed section.

Solid fuel 512 can be applied to a portion of substrates 510 as a thinfilm or layer. The thickness of the thin layer of solid fuel 512, andthe composition of solid fuel 512 can determine the maximum temperatureas well as the temporal and spatial dynamics of the temperature profileproduced by the burning of the solid fuel.

Studies using thin solid fuel layers having a thickness ranging from0.001 inches to 0.005 inches demonstrate that the maximum temperaturereached by a thin film substrate on which the solid fuel is disposed canbe linear with the mass of solid fuel applied. For example, as shown inFIG. 12 for several different solid fuel compositions, for a 0.001 inchto 0.003 inch thick layer of Zr/MoO₃ solid fuel having a mass rangingfrom 0.13 g to 0.25 g, the maximum temperature reached by the substrateduring burn is linear. Other studies with solid fuel layers having amass ranging from 0.12 g to 0.24 g demonstrate linearity over atemperature ranging from 375° C. to 625° C. It will be appreciated thatone skilled in the art can establish similar relationships for othersolid fuel compositions and configurations. Such studies demonstratethat the temperature reached by the substrate when the solid fuel isburned can be established by controlling the amount of solid fuelapplied to the substrate.

Measurements of the substrate surface temperature demonstrate that thincoatings of a solid fuel comprising a metal reducing agent and ametal-containing oxidizing agent can produce homogenous heating. Atemperature profile of a substrate forming a heating unit substantiallyas shown in FIGS. 10A and 10B and described in Example 9 followingignition of the solid fuel is shown in FIG. 19. FIG. 19 shows theaverage surface temperature at various positions across two dimensionsof a 1.3 inch×1.3 inch substrate 0.25 seconds following ignition of a0.00163 inch thick coating of solid fuel. The average surfacetemperature of the effective heated area was about 400° C. In certainembodiments, the average surface temperature of a 1.3 inch×1.3 inchsubstrate heated by a thin coating of solid fuel can exhibit a standarddeviation ranging from about 8° C. to 50° C.

Measurements of the substrate surface temperature after firingdemonstrate that thin coatings or layers of a solid fuel comprising ametal reducing agent and a metal-containing oxidizing agent can produceuniformity of temperature on the exterior surface of the substrate.Uniformity of temperature is defined herein to exist when thetemperature in degrees Celsius of the exterior surface of the substrate,corresponding to the fuel coated area of the interior surface of thesubstrate, is within a standard deviation of 50° C. from the averagesurface temperature obtained, as measured within 100 milliseconds aftercompletion of propagation of the ignited fuel flame front. A temperatureprofile of a substrate forming a heating unit substantially as shown inFIGS. 10A and 10B and described in Example 9 following ignition of thesolid fuel is shown in FIG. 19. FIG. 19 shows the average surfacetemperature at various positions across two dimensions of a 1.3 inch×1.3inch substrate 0.25 seconds following ignition of a 0.00163 inch thickcoating of solid fuel.

In certain applications, such as for example, vaporization of a drug offthe substrate of a heating unit, uniformity of heating of the substrateis critical as it facilitates the production of an aerosol comprising ahigh purity drug or pharmaceutical composition and maximizes the yieldof drug initially deposited on the substrate forming an aerosol.

In certain embodiments, solid fuel 512 can comprise a mixture ofZr/MoO₃, Zr/Fe₂O₃, Al/MoO₃, or Al/Fe₂O₃. In certain embodiments, theamount of metal reducing agent can range from 60 wt % to 90 wt %, andthe amount of metal-containing oxidizing agent can range from 40 wt % to10 wt %. In certain embodiments, higher ratios of metal reducing agentcan cause the solid fuel to burn slower and at a lower temperature,whereas lower ratios of metal reducing agent can cause the solid fuel toburn faster and reach a higher maximum temperature. Regardless of theweight percent ratios of the metal reducing agent and metal-containingoxidizing agent, a solid fuel can comprise a stoichiometric amount ofmetal reducing agent and metal-containing oxidizing agent. For example,the balanced Zr:Fe₂O₃ metal oxidation-reduction reaction can be writtenas:3Zr+2Fe₂O₃→3ZrO₂+4FeA stoichiometric amount of Zr:Fe₂O₃ for this reaction is 1:1.67 byweight.

Drug 514 can be disposed on the exterior surface of substrates 510. Theamount of drug 514 disposed on the exterior surface of substrate 510 canbe any appropriate amount. For example, the amount of drug 514 can be atherapeutically effective amount. A therapeutically effective amount canbe determined by the potency of the drug, the clinical indications, andthe mode of administration. In certain embodiments, thin film drugsupply unit can be configured to thermally vaporize more than 95% of thedrug, and in certain embodiments, greater than 98% of the drug, withminimal degradation of the drug. The aerosol formed using a drug supplyunit can comprise greater than 90% of a drug applied to a substrate, andin certain embodiments greater than 95% of a drug applied to asubstrate. The yield and purity of the aerosol can be controlled by andselected based on the temporal characteristics and magnitude of thethermal impulse transferred to the compound.

The relationship of the yield and purity of an aerosol comprising apharmaceutical compound on the substrate temperature and mass of solidfuel for certain embodiments is shown in FIG. 18. Thin film drug supplyunits substantially as shown in FIGS. 10A and 10B, and described inExample 9 were used to produce the measurements shown in FIG. 18. Theexperimental arrangement used to analyze the percent yield and percentpurity of the aerosol comprising a vaporized drug is described inExample 10. As shown in FIG. 18, at substrate temperatures ranging fromabout 355° C. to about 425° C., the percent yield of drug forming theaerosol was greater than about 85% and the percent purity was greaterthan about 90%. The percent yield refers to the ratio of the total solidweight of the aerosol to the weight of the drug initially deposed on thesubstrate times 100. Factors that can reduce the percent yield includeincomplete vaporization of the drug and redeposition of the drug on thesubstrate.

The percent purity, with respect to the aerosol purity, refers to thefraction of drug composition in the aerosol/the fraction of drugcomposition in the aerosol plus drug degradation products times 100.Thus purity is relative with regard to the purity of the startingmaterial. For example, when the starting drug or drug composition usedfor substrate coating contained detectable impurities, the reportedpurity of the aerosol does not include those impurities present in thestarting material that were also found in the aerosol, e.g., in certaincases if the starting material contained a 1% impurity and the aerosolwas found to contain the identical 1% impurity, the aerosol purity maynevertheless be reported as >99% pure, reflecting the fact that thedetectable 1% purity was not produced during thevaporization-condensation aerosol generation process.

Factors that can reduce the percent purity of the aerosol includedegradation of the drug during thermal vaporization. Depending at leastin part on the composition and thermal properties of a particular drugor pharmaceutical composition, the appropriate thermal vaporizationtemperature to produce an aerosol comprising the particular drug orpharmaceutical composition having high yield and purity can bedetermined as set forth in U.S. application Ser. No. 10/718,982, filedNov. 20, 2003.

Drug 514 can be applied to substrate 510 using any appropriate method,such as for example, brushing, dip coating, screen printing, rollercoating, spray coating, inkjet printing, stamping, vapor deposition, andthe like. Drug 514 can also be applied to a support having a releaselayer and transferred to substrate 510. Drug 514 can be suspended in avolatile solvent such as, for example, but not limited to, acetone orisopropanol to facilitate application. A volatile solvent can be removedat room temperature or at elevated temperature, with or withoutapplication of a vacuum. In certain embodiments, the solvent cancomprise a pharmaceutically acceptable solvent. In certain embodiments,residual solvent can be reduced to a pharmaceutically acceptable level.

Drug 514 can be disposed on substrate 510 in any appropriate form suchas a solid, viscous liquid, liquid, crystalline solid, or powder. Incertain embodiments, the film of drug can be crystallized afterdisposition on the substrate.

As shown in FIGS. 10A-10B, a drug supply unit can comprise an igniter520. In certain embodiments, igniter 520 can comprise an initiatorcomposition 522 disposed on an electrically resistive heating elementconnected to electrical leads disposed between two strips of insulatingmaterials (not shown). The electrical leads can be connected to a powersource (not shown). Initiator composition 522 can comprise any of theinitiator compositions or compositions described herein. In certainembodiments, the ignition temperature of initiator composition can rangefrom 200° C. to 500° C. The electrically resistive material can comprisea material capable of generating heat when electrical current isapplied. For example, the electrically resistive material can be a metalsuch as nichrome, tungsten or graphite. An initiator composition can bedisposed on the surface of the electrically resistive material such thatwhen the electrically resistive material is heated to the ignitiontemperature of the initiator composition, the initiator composition canignite to produce sparks. An initiator composition can be applied to theelectrically resistive heating element by depositing a slurry comprisingthe initiator composition and drying. In certain embodiments, aninitiator composition can be deposited on a solid fuel at a positionsuch that when assembled, the initiator composition forming the igniteris adjacent to the initiator composition deposited on the solid fuel.Having initiator composition on at least a portion of the solid fuel canincrease the speed of ignition and the reliability of the ignitionprocess.

The electrically resistive heating element can be connected toelectrical conductors. The heating element can be soldered orelectrically connected to conductors, such as, Cu conductors or graphiteink traces, disposed on an electrically insulating substrate, such as apolyimide, polyester, or fluoropolymer. The conductors can be disposedbetween two opposing layers of the electrically insulating material suchas flexible or rigid printed circuit board materials. The heatingelement on which an initiator composition is disposed can be exposedthrough an opening in the end of ignition assembly 520.

Igniter 520 can be positioned with respect to solid fuel 512 such thatsparks produced by initiator composition 522 can be directed towardsolid fuel area 512, causing solid fuel 512 to ignite and burn.Initiator composition 522 can be located in any position such thatsparks produced by the initiator can cause solid fuel 512 to ignite. Thelocation of initiator composition 522 with respect to solid fuel 512 candetermine the direction in which solid fuel 512 burns. For example,initiator composition 522 can be located to cause solid fuel 512 to burnin any direction with respect to the airflow including in the samedirection of airflow, opposite the direction of airflow, or normal thedirection of airflow. The direction of solid fuel burn with respect toairflow can influence the average particle diameter of particulatescomprising the thermally vaporized drug forming the aerosol. Forexample, in certain embodiments, solid fuel burn opposite the directionof airflow can produce smaller diameter particles than when thedirection of solid fuel burn is in the same direction as the airflow.The dynamics of solid fuel burn can be influenced by other parameterssuch as the spatial and temporal characteristics of the surfacetemperature, and the extent to which vaporized drug is redeposited onthe substrate and/or other surfaces such as a housing in which the drugsupply unit is incorporated.

In certain embodiments, thin film drug supply unit 500 can comprise morethan one igniter 520 and/or each igniter 520 can comprise more than oneinitiator composition 522.

In certain embodiments, it can be useful to minimize the amount ofinitiator composition used, so as to reduce the amount of gas and otherreaction products potentially generated by the initiator compositionduring burn.

In certain embodiments, igniter 520 can comprise a mechanism configuredto direct transmitted radiation to an initiator composition capable ofabsorbing and being heated by the transmitted radiation, to producesparks. For example, in certain embodiments, the radiation can beinfrared, visible, or ultraviolet radiation such as produced by a diodelaser, light emitting diode, or flashlamp. Radiation produced by aradiation source can be transmitted through a waveguide such as anoptical fiber, and directed to an initiator or the radiation source canbe incorporated into the ignition assembly 522 with electricalconductors for connecting to an external power source. The transmissiondevice can include elements such as lenses for focusing the transmittedradiation onto the initiator composition. In certain embodiments, theradiation can be directed to an initiator composition disposed withinthe heating unit through a window. The transmitted radiation can bedirected onto an absorber or a material capable of absorbing theradiation, which can be the initiator composition, or an element onwhich the initiator composition is disposed. In certain embodiments, theinitiator composition can comprise at least one metal such as, but notlimited to, zirconium, titanium, or aluminum, and at least one solidoxidizer such as, but not limited to, MoO₃, KClO₄, CuO, or WO₃. Theinitiator composition can comprise any of those disclosed herein.

As shown in FIG. 10A, thin film drug supply unit 500 can have a spacer518. Spacer 518 can retain igniter 520. In certain embodiments, spacer518 can provide a volume or space within the interior of thin filmheating unit 500 to collect gases and byproducts generated during theburn of the initiator composition 522 and solid fuel 512. The volumeproduced by spacer 518 can reduce the internal pressure within thin filmdrug supply unit 500 upon ignition of the fuel. In certain embodiments,the volume can comprise a porous or fibrous material such as a ceramic,or fiber mat in which the solid matrix component is a small fraction ofthe unfilled volume. The porous or fibrous material can provide a highsurface area on which reaction products generated during the burning ofthe initiator composition and the solid fuel can be absorbed, adsorbedor reacted. The pressure produced during burn can in part depend on thecomposition and amount of initiator composition and solid fuel used. Incertain embodiments, the spacer can be less than 0.3 inches thick, andin certain embodiments less than 0.2 inches thick. In certainembodiments, the maximum internal pressure during and following burn canbe less than 50 psig, in certain embodiments less than 20 psig, incertain embodiments less than 10 psig, and in other certain embodimentsless than 6 psig. In certain embodiments, the spacer can be a materialcapable of maintaining structural and chemical properties at thetemperatures produced by the solid fuel burn. In certain embodiments,the spacer can be a material capable of maintaining structure andchemical properties up to a temperature of about 100° C. It can beuseful that the material forming the spacer not produce and/or releaseor produce only a minimal amount of gases and/or reaction products atthe temperatures to which it is exposed by the heating unit. In certainembodiments, spacer 518 can comprise a metal, a thermoplastic, such as,for example, but not limitation, a polyimide, fluoropolymer,polyetherimide, polyether ketone, polyether sulfone, polycarbonate,other high temperature resistant thermoplastic polymers, or a thermoset,and which can optionally include a filler.

In certain embodiments, spacer 518 can comprise a thermal insulator suchthat the spacer does not contribute to the thermal mass of the thin filmdrug supply unit thereby facilitating heat transfer to the substrate onwhich drug 514 is disposed. Thermal insulators or impulse absorbingmaterials such as mats of glass, silica, ceramic, carbon, or hightemperature resistant polymer fibers can be used. In certainembodiments, spacer 518 can be a thermal conductor such that the spacerfunctions as a thermal shunt to control the temperature of thesubstrate.

Substrates 510, spacer 518 and igniter 520 can be sealed. Sealing canretain any reactants and reaction products released by burning ofinitiator composition 522 and solid fuel 514, as well as provide aself-contained unit. As shown in FIG. 10A, substrates 510 can be sealedto spacer 518 using an adhesive 516. Adhesive 516 can be a heatsensitive film capable of bonding substrates 510 and spacer 518 upon theapplication of heat and pressure. In certain embodiments, substrates 510and spacer 518 can be bonded using an adhesive applied to at least oneof the surfaces to be bonded, the parts assembled, and the adhesivecured. The access in spacer 518 into which igniter 520 is inserted canalso be sealed using an adhesive. In certain embodiments, other methodsfor forming a seal can be used such as for example, welding, soldering,or fastening.

In certain embodiments, the elements forming the thin film drug supplyunit 500 can be assembled and sealed using thermoplastic or thermosetmolding methods such as insert molding and transfer molding.

An appropriate sealing method can, at least in part be determined by thematerials forming substrate 510 and spacer 518. In certain embodiments,drug supply unit 500 can be sealed to withstand a maximum pressure ofless than 50 psig. In certain embodiments less than 20 psig, and incertain embodiments less than 10 psig. In certain embodiments, thematerials used to form the seal can maintain structural integrity at thetemperature reached by the article. In certain embodiments, thematerials used can exhibit minimal degradation and produce minimalgaseous reaction products at the temperature reached by the heatingunit.

Multidose Drug Supply Units

In certain embodiments, a drug supply unit can be configured for use insingle-use devices or in multi-use devices. FIGS. 9A-9B illustratecertain embodiments of drug supply units configured for use in a drugdelivery device designed for multiple uses. As shown in FIG. 9A, a tape406 in the form of a spool or reel 400 comprises a plurality of drugsupply units 402, 404. The plurality of drug supply units 402, 404 cancomprise a heating unit on which is disposed a thin film of a drug to bethermally vaporized. Each of the plurality of drug supply units 402, 404can comprise the same features as those described herein, for example,in FIG. 1A and/or FIG. 1B. In certain embodiments, tape 406 can comprisea plurality of heating units. Each heating unit can comprise a solidfuel, an initiator composition, and a substrate.

Embodiments of thin film drug supply units are schematically illustratedin FIGS. 11A-11B. FIGS. 11A-11B illustrate certain embodiments whereinthe thin film drug supply units 600 are in the form of a tape 650comprising multiple layers. As shown in FIG. 11A, tape 650 comprises afirst layer 601 having openings in which a drug to be thermallyvaporized 610 is disposed. A second layer 602 underlying first layer 601separates drug 610 from solid fuel 620 disposed within a third layer 603underlying second layer 602. Second layer 602 can be thermallyconductive such that heat can be efficiently transferred from solid fuel620 to compound 610. In certain embodiments, second layer 602 can be anyof the metals described herein. Regions comprising solid fuel 620underlie regions comprising drug 610. The amount of solid fuel 620 canbe an amount sufficient to thermally vaporize drug 610. The dimensionsand geometry of the region comprising solid fuel 620 can be anyappropriate dimension. In certain embodiments, third layer 603 cancomprise a volume 640 to collect reaction products generated during burnof solid fuel 620 and thereby reduce the pressure within thin film drugsupply unit 600. In certain embodiments (not shown), volume 640 cancomprise a material capable of absorbing, adsorbing or reacting withreaction products produced during burning of the solid, such as a porousceramic or fibrous material. Third layer 603 can comprise a material inwhich the mechanical properties are substantially maintained and whichwill not appreciably chemically degrade up to the temperatures reachedby the drug supply unit 600. In certain embodiments, third layer 603 cancomprise a metal or a polymer such as polyimide, fluoropolymer,polyetherimide, polyether ketone, polyether sulfone, polycarbonate, orother high temperature resistance polymers.

In certain embodiments, tape 650 can comprise an upper and lower layer(not shown) configured to physically and/or environmentally protectcompound 610 and solid fuel 620. The upper and/or lower protectivelayers can comprise, for example, a metal foil, a polymer, or cancomprise a multilayer comprising metal foil and polymers. In certainembodiments, protective layers can exhibit low permeability to oxygen,moisture, and/or corrosive gases. All or portions of a protective layercan be removed prior to use to expose compound 610 and solid fuel 620.To vaporize compound 610, solid fuel 620 can be ignited by energy froman external source (not shown) to generate heat that can be conductedthrough second layer 602 to thermally vaporize compound 610. Examples ofinitiators include those discussed herein such as, but not limited to,sparks or electrical resistance heating. Use of a protective layer canfacilitate use of drug 610 in the form of a powder or liquid.

FIG. 11B shows a cross-sectional view of a tape 670 comprising thin filmdrug supply units 600, which in addition to the elements recited forFIG. 11A, further comprise an initiator composition 630. Tape 670 hasmultiple layers including first layer 601 within which compound 610 isdisposed, second layer 602 separating first layer 601 and third layer603. Layer 603 retains solid fuel 620 and in certain embodiments, avolume 640. Openings in a fourth layer 604 define a gap separating solidfuel 620 disposed in third layer 603, and initiator composition 630disposed within regions of a fifth layer 605. Initiator composition 630can comprise any of the initiator compositions disclosed herein.Initiator 630 can adjoin an electrically resistive heating element 682disposed within a sixth layer 606 and connected to electrical conductors680 also disposed within sixth layer 606. As shown, a seventh layer 607overlies sixth layer 606 and comprises openings 617 to facilitateelectrical connection between electrical conductors 680 and a powersource (not shown).

In an exemplary operation, tape 670 can be advanced to locate at leastone region comprising drug 610 within an airway (not shown) and toconnect respective electrical contacts 680, with a power source (notshown). Upon activation of the power source, the electrical current canheat resistive element 682 to ignite initiator composition 630 andproduce sparks. Sparks directed across gap 645 can ignite solid fuel620. Heat generated by the ignition of solid fuel 620 can be conductedthrough second layer 602 thermally vaporizing compound 610 to form anaerosol comprising drug 610 within the airway.

Certain embodiments of another drug supply article configured for thedelivery of multiple doses is illustrated in FIG. 9B. FIG. 9B shows aplurality of individual drug-supply units provided on a card 410. Drugsupply units 412, 414, 416, each consist of a solid fuel containedbetween a backing member and a substrate, such as substrate 418 on unit412. A film of drug can be coated onto substrate 418. Card 410 can beloaded into a suitable device configured to ignite at least one drugsupply unit at a time. Ignition can be, for example by sparks, asdisclosed herein. To provide a subsequent dose, card 410 can be rotatedto advance a fresh drug supply unit.

FIG. 9C shows a cartridge 420 containing a plurality ofcylindrically-shaped drug supply units 422, 424, 426, 428. The drugsupply units can be as described herein, and comprise a solid fuelcontained within an enclosure comprising a substrate. The externalsurface of the substrate can be coated with a film of drug. Each drugsupply unit can be successively advanced into position in a drugdelivery device chamber for ignition of the solid fuel, vaporization ofthe drug, and administration to a user.

Drug Delivery Devices

Certain embodiments include drug delivery devices comprising a housingdefining an airway, a heating unit as disclosed herein, a drug disposedon a portion of the exterior surface of a substrate of the heating unit,wherein the portion of the exterior surface comprising the drug isconfigured to be disposed within the airway, and an initiator configuredto ignite the solid fuel. Drug delivery devices can incorporate theheating units and drug supply units disclosed herein. The drug deliverydevice can comprise a housing defining an airway. The housing can definean airway having any appropriate shape or dimensions and can comprise atleast one inlet and at least one outlet. The dimensions of an airway canat least in part be determined by the volume of air that can be inhaledthrough the mouth or the nostrils by a user in a single inhalation, theintended rate of airflow through the airway, and/or the intended airflowvelocity at the surface of the substrate that is coupled to the airwayand on which a drug is disposed. In certain embodiments, airflow can begenerated by a patient inhaling with the mouth on the outlet of theairway, and/or by inhaling with the nostrils on the outlet of theairway. In certain embodiments, airflow can be generated by injectingair or a gas into the inlet such as for example, by mechanicallycompressing a flexible container filled with air and/or gas, or byreleasing pressurized air and/or gas into the inlet of the airway.Generating an airflow by injecting air and/or gas into the airway can beuseful in drug delivery devices intended for topical administration ofan aerosol comprising a drug.

In certain embodiments, a housing can be dimensioned to provide anairflow velocity through the airway sufficient to produce an aerosol ofa drug during thermal vaporization. In certain embodiments, the airflowvelocity can be at least 1 msec in the vicinity of the substrate onwhich the drug is disposed.

In certain embodiments, a housing can be dimensioned to provide acertain airflow rate through the airway. In certain embodiments, theairflow rate through the airway can range from 10 L/min to 120 L/min. Incertain embodiments, an airflow rate ranging from 10 L/min to 120 L/mincan be produced during inhalation by a user when the outlet exhibits across-sectional area ranging from 0.1 cm² to 20 cm². In certainembodiments, the cross-sectional area of the outlet can range from 0.5cm² to 5 cm², and in certain embodiments, from 1 cm² to 2 cm².

In certain embodiments, an airway can comprise one or more airflowcontrol valves to control the airflow rate and airflow velocity inairway. In certain embodiments, an airflow control valve can comprise,but is not limited to, at least one valve such as an umbrella valve, areed valve, a flapper valve, or a flapping valve that bends in responseto a pressure differential, and the like. In certain embodiments, anairflow control valve can be located at the outlet of the airway, at theinlet of the airway, within the airway, and/or can be incorporated intothe walls of housing defining the airway. In certain embodiments, anairflow control valve can be actively controlled, for example can beactivated electronically such that a signal provided by a transducerlocated within the airway can control the position of the valve; orpassively controlled, such as, for example, by a pressure differentialbetween the airway and the exterior of the device.

Certain embodiments of drug delivery devices configured for inhalationdelivery of thermal vapor generated from a drug supply unit areillustrated in FIG. 8. Inhalation device 150 has an upper externalhousing member 152 and a lower external housing member 154 that snap fittogether. The downstream end of each housing member can be gentlytapered for insertion into a user's mouth, as shown on upper housingmember 152 at downstream end 156. The upstream end of the upper andlower housing members can be slotted 158, as shown in the upper housingmember 152, to provide for air intake when a user inhales. When fittedtogether, upper and lower housing members 152, 154 define a chamber 160.A drug supply unit 162 can be positioned within chamber 160. Drug supplyunit 162 comprises a tapered, substantially cylindrical substrate 164having an external surface 168 on which is disposed a film 166 of drug.The interior surface 170 of the substrate and a portion of the inner,cylindrical backing member 172 are shown in the cut-away section of drugsupply unit 162. Solid fuel 174 is located within the annular shellregion defined by backing member 172 and interior substrate surface 170.At least one initiator composition can be provided for the heating unit,and in certain embodiments as shown in FIG. 8, an initiator compositioncan be positioned (not shown) in the upstream end of the device wherethe air intake occurs. The initiator composition can be configured toignite solid fuel 174 by the application of electrical current to anohmic heating element connected to a battery (not shown) located in endpiece 176. Activation of the initiator composition can produce sparksthat are confined within a space defined by backing member 172 and thuscan be directed toward the downstream end of the drug supply unitindicated at point 178. Sparks reaching the tapered nose portion atdownstream end 178 can ignite solid fuel 174. Solid fuel 174 then burnsin a downstream-to-upstream direction, i.e. from point 178 toward theair intake end of the device at point 158, generating a wave of heat inthe downstream-to-upstream direction that vaporizes drug film 166disposed on exterior substrate surface 168. Thus, the direction of solidfuel burn and the direction of thermal drug vapor generation areopposite the direction of airflow through chamber 160 of the inhalationdevice.

Methods for Producing and Using Aerosols

Certain embodiments include methods of producing an aerosol of acompound using the heating units, drug supply units, and drug deliverydevices disclosed herein. In certain embodiments, the aerosol producedby an apparatus can comprise a therapeutically effective amount of adrug. The temporal and spatial characteristics of the heat applied tothermally vaporize the compound disposed on the substrate and the airflow rate can be selected to produce an aerosol comprising a drug havingcertain characteristics. For example, for intrapulmonary delivery it isknown that aerosol particles having a mean mass aerodynamic diameterranging from 0.01 μm to 0.1 μm and ranging from 1 μm to 3.5 μm canfacilitate efficient transfer of drugs from alveoli to the systemiccirculation. In applications wherein the aerosol is applied topically,the aerosol can have the same or different characteristics.

Certain embodiments include methods for producing an aerosol comprising:(i) providing an airflow over a drug disposed on a portion of anexterior surface of a substrate forming a drug supply unit, wherein thedrug supply unit comprises a heating unit as disclosed herein and thedrug disposed on a portion of the exterior surface of the substrate,wherein the portion of the exterior surface comprising the drug isdisposed within the airway; and an initiator composition configured toignite the solid chemical fuel; and (ii) thermally vaporizing andcondensing the drug to form an aerosol of the drug in the airway. Incertain embodiments, the drug is disposed on the surface of thesubstrate as a thin film.

Certain embodiments include methods of treating a disease in a patientin need of such treatment comprising administering to the patient anaerosol comprising a therapeutically effective amount of a drug, whereinthe aerosol is produced by the methods and devices disclosed herein. Theaerosol can be administered by inhalation through the mouth, by nasalingestion, and/or by topical application.

Other embodiments will be apparent to those skilled in the art fromconsideration and practice of the invention disclosed herein. It isintended that the specification and examples be considered as exemplaryonly.

EXAMPLES

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

wt % weight percent psig pounds per square inch, gauge DI deionized mLmilliliters msec milliseconds L/min liters per minute μm micrometer

Example 1 Preparation of Solid Fuel with LAPONITE

The following procedure was used to prepare solid fuel coatingscomprising 76.16% Zr:19.04% MoO₃:4.8% LAPONITE® RDS.

To prepare wet Zirconium (Zr), the as-obtained suspension of Zr in DIwater (Chemetall, Germany) was agitated on a roto-mixer for 30 minutes.Ten to 40 mL of the wet Zr was dispensed into a 50 mL centrifuge tubeand centrifuged (Sorvall 6200RT) for 30 minutes at 3,200 rpm. The DIwater was removed to leave a wet Zr pellet.

To prepare a 15% LAPONITE® RDS solution, 85 grams of DI water was addedto a beaker. While stirring, 15 grams of LAPONITE® RDS (Southern ClayProducts, Gonzalez, Tex.) was added, and the suspension stirred for 30minutes.

The reactant slurry was prepared by first removing the wet Zr pellet aspreviously prepared from the centrifuge tube and placed in a beaker.Upon weighing the wet Zr pellet, the weight of dry Zr was determinedfrom the following equation: Dry Zr (g)=0.8234 (Wet Zr (g))−0.1059.

The amount of molybdenum trioxide to provide a 80:20 ratio of Zr to MoO₃was then determined, e.g, MoO₃=Dry Zr (g)/4, and the appropriate amountof MoO₃ powder (Accumet, N.Y.) was added to the beaker containing thewet Zr to produce a wet Zr:MoO₃ slurry. The amount of LAPONITE® RDS toobtain a final weight percent ratio of dry components of 76.16%Zr:19.04% MoO₃:4.80% LAPONITE® RDS was determined Excess water to obtaina reactant slurry comprising 40% DI water was added to the wet Zr andMoO₃ slurry. The reactant slurry was mixed for 5 minutes using an IKAUltra-Turrax mixing motor with a S25N-8G dispersing head (setting 4).The amount of 15% LAPONITE® RDS previously determined was then added tothe reactant slurry, and mixed for an additional 5 minutes using the IKAUltra-Turrax mixer. The reactant slurry was transferred to a syringe andstored for at least 30 minutes prior to coating.

The Zr:MoO₃:LAPONITE® RDS reactant slurry was then coated onto stainlesssteel foils. Stainless steel foils were first cleaned by sonication for5 minutes in a 3.2% by solution of Ridoline 298 in DI water at 60° C.Stainless steel foils were masked with 0.215 inch wide MYLAR® such thatthe center portion of each 0.004 inch thick 304 stainless steel foil wasexposed. The foils were placed on a vacuum chuck having 0.008 inch thickshims at the edges. Two (2) mL of the reactant slurry was placed at oneedge of the foil. Using a Sheen Auto-Draw Automatic Film Applicator 1137(Sheen Instruments) the reactant slurry was coated onto the foils bydrawing a #12 coating rod at an auto-draw coating speed of up to 50mm/sec across the surface of the foils to deposit approximately an 0.006inch thick layer of the Zr:MoO₃:LAPONITE® RDS reactant slurry. Thecoated foils were then placed in a 40° C. forced-air convection oven anddried for at least 2 hours. The masks were then removed from the foilsto leave a coating of solid fuel on the center section of each foil.

The solid fuel coatings comprising LAPONITE® RDS adhered to thestainless steel foil surface and maintained physical integrity followingmechanical and environmental testing including temperature cycling (−25°C.

40° C.), accelerated humidity exposure (40° C./75% RH), drop testing,impact testing, and flexure testing.

Example 2 Measurement of Internal Pressure

Thin film heating units were used to measure the peak internal pressureand the peak temperature of the exterior surface of the substratefollowing ignition of the solid fuel.

The thin film heating units were substantially as described in Example 9below and as illustrated in FIGS. 10A and 10B. Two, 2×2 square inch,0.004 inch thick 304 stainless steel foils formed the substrates. Asolid fuel comprising 76.16 wt % Zr, 19.04% MoO₃, 4.8% LAPONITE® RDS andwater was coated onto the interior surface of the stainless steelsubstrates. The thickness of the solid fuel layer was 0.0018±0.0003inches. The layer of solid fuel covered an area of 1.69 in² and afterdrying, the weight of the solid fuel disposed on the interior surface ofeach substrate was 0.165 to 0.190 grams. The spacer comprised a 0.24inch thick section of polycarbonate (Makrolon). The ignition assemblycomprised a FR-4 printed circuit board having a 0.03 inch diameteropening at the end to be disposed within an enclosure defined by thespacer and the substrates. A 0.0008 inch diameter Nichrome wire wassoldered to electrical conductors on the printed circuit board andpositioned across the opening. An initiator composition comprising 26.5%Al, 51.4% MoO₃, 7.7% B and 14.3% VITON® A500 weight percent wasdeposited onto the Nichrome wire and dried.

To assemble the thin film drug supply unit, the Nichrome wire comprisingthe initiator composition was positioned at one end of the solid fuelarea. A bead of epoxy (Epo-Tek 353 ND, Epoxy Technology) was applied toboth surfaces of the spacer, and the spacer, substrates and the ignitionassembly positioned and compressed. The epoxy was cured at a temperatureof 100° C. for 3 hours.

To ignite the solid fuel, a 0.4 amp current was applied to theelectrical conductors connected to the Nichrome wire.

The peak internal pressure was measured using a pressure sensor(Motorola, MPXA4250A) The external surface temperature was measuredusing IR camera (FLIR, Therma CAM SC3000).

Example 3 Thermal Images of Heating Unit

A solid fuel consisting of a mixture of zirconium (40.6 wt %), MoO₃(21.9 wt %), and KClO₃ (1.9 wt %), nitrocellulose (0.6 wt %), anddiatomaceous earth (35 wt %) was prepared. The solid fuel was placed ina 0.030-inch gap between a stainless steel substrate (0.015 inch wallthickness) and a stainless steel backing member (0.015 inch wallthickness). The diameter of the substrate was 9/16 inch. The fuel wasignited, and thermal images of the heating unit were taken as a functionof time after ignition. The results are shown in FIGS. 4A-4F.

Example 4 Thermal Images of Heating Units to Evaluate SurfaceTemperature Uniformity

A. A solid fuel consisting of a mixture of zirconium (53.8 wt %), MoO₃(23.1 wt %), and KClO₃ (2.3 wt %), nitrocellulose (0.8 wt %) anddiatomaceous earth (20 wt %), was prepared. The solid fuel mixture wasplaced in a 0.030-inch gap between a stainless steel substrate (0.015inch wall thickness) and a stainless steel backing member (0.015 inchwall thickness). The diameter of the substrate was 9/16 inch. The fuelwas ignited, and a thermal image of the heating unit was taken 400milliseconds after ignition. The image is shown in FIG. 5A.

B. A solid fuel consisting of a mixture of zirconium (46.9 wt %), MoO₃(25.2 wt %), KClO₃ (2.2 wt %), nitrocellulose (0.7 wt %), anddiatomaceous earth (25.0 wt %) was prepared. The solid fuel was placedin a 0.030-inch gap between a stainless steel substrate (0.015 inch wallthickness) and a stainless steel backing member (0.015 inch wallthickness). The diameter of the substrate was 9/16 inch. The fuel wasignited, and a thermal image of the heating unit was taken 400milliseconds after ignition. The image is shown in FIG. 5B.

Example 5 Exemplary Heating Unit

A solid fuel consisting of a mixture of zirconium (46.9 wt %), MoO₃(25.2 wt %), and KClO₃ (2.2 wt %), grain size 100-325 mesh, along withnitrocellulose (0.7 wt %) and diatomaceous earth (25.0 wt %) wasprepared. The solid fuel was placed in a 0.030-inch gap between astainless steel substrate (0.015 inch wall thickness) and a stainlesssteel backing member (0.015 inch wall thickness). The diameter of thesubstrate was 9/16 inch. The solid fuel was remotely ignited from thetip of the heating unit. During and after burn, the pressure in thecylindrical substrate was measured as described herein. The burnpropagation speed and the surface temperature uniformity were evaluatedby infrared imaging.

The internal pressure increased to 150 psig during the reaction periodof 0.3 seconds. The residual pressure was under 60 psig. The burnpropagation speed was 13 cm/sec. With respect to surface temperatureuniformity, no obvious cold spots were observed.

Example 6 Heating Unit Embodiment

A solid fuel consisting of a mixture of zirconium (69.3 wt %) and MoO₃(29.7 wt %), grain size 100-325 mesh, along with nitrocellulose (1.0 wt%) was prepared. The solid fuel mixture was placed in a 0.020-inch gapbetween a stainless steel substrate (0.020 inch wall thickness) and astainless steel backing member (0.020 inch wall thickness). The outsideof the backing member was coated with initiator to increase burnpropagation speed. The primary fuel was remotely ignited from the tip ofthe heating unit. During and after burn, the pressure in the cylindricalsubstrate was measured as described herein. The burn propagation speedand the surface temperature uniformity were evaluated by infraredimaging.

The internal pressure increased to 200 psig during the reaction periodof 0.25 seconds. The residual pressure was under 60 psig. The burnpropagation speed was 15 cm/sec. With respect to surface temperatureuniformity, no obvious cold spots were observed.

Example 7 Heating Unit Embodiment

A solid fuel consisting of a mixture of aluminum (49.5 wt %) and MoO₃(49.5 wt %), grain size 100-325 mesh, along with nitrocellulose (1.0 wt%) was prepared. The solid fuel mixture was placed in a 0.020-inch gapbetween a stainless steel substrate (0.020 inch wall thickness) and astainless steel backing member (0.020 inch wall thickness). The primaryfuel was directly ignited near the plug. During and after burn, thepressure in the cylindrical substrate was measured as described herein.The surface temperature uniformity was evaluated by infrared imaging.

The internal pressure increased to 300 psig during the reaction periodof less than 5 milliseconds. The residual pressure was under 60 psig.The exterior surface expanse was uniformly heated, with between 5-10percent of the surface being 50° C. to 100° C. cooler than the rest ofthe expanse.

Example 8 Wet Processing for Zirconium Fuel Slurry

The following procedure was used to prepare fuel compositions comprisingZr and MoO₃ for a thin film drug supply unit. Wet Zr particles, 46.7 wt%, having a 2 μm to 3 μm particle size were obtained from Chemetall,GmbH, Germany. The Zr particles were rinsed with DI water, followingwhich the excess water was decanted. DI water, 5.1 wt %, was added tothe Zr and the mixture centrifuged. Excess water was decanted. Dry MoO₃,20 wt %, (Climax Molybdenum Co., AZ) and DI water was then added to thewashed Zr, and the mixture homogenized for 2 minutes with a high shearmixer (IKA, Germany). A 15% aqueous solution of LAPONITE® RDS, 2.5 wt %,(Southern Clay Products, Inc., Texas) was added and the mixturehomogenized with a high shear mixer for an additional 5 minutes. TheZr:MO₃ solid fuel slurry was transferred to a syringe or holding vesselfor subsequent coating. The wet Zr included 8.5 wt % water and theLAPONITE® RDS gel included 14 wt % water. The weight percents representthe percent weight of the total wet composition.

Example 9 Thin Film Drug Supply Unit Embodiment

A thin film drug supply unit according to FIGS. 10A-10B was fabricatedand the performance evaluated. Two, 2×2 square inch, 0.004 inch thick304 stainless steel foils formed the substrates. A solid fuel comprising76.16 wt % Zr and 19.04% MoO₃ and 4.8% LAPONITE® RDS and water wascoated onto the interior surface of the stainless steel substrates. Thethickness of the solid fuel layer was 0.0018±0.0003 inches. The layer ofsolid fuel covered an area of 1.69 in² and after drying, the weight ofthe solid fuel disposed on the interior surface of each substrate was0.165 to 0.190 grams. An ˜6 μm thick thin film of a drug was depositedonto a 1.21 in² area of the exterior substrate surfaces using spraycoating. The drug was dissolved in a 15 mg/ml solution of isopropanol oracetone to facilitate processing. The thin film of drug was dried atambient conditions and 1.5 mg to 3.0 mg of drug was deposited on theexterior surface of each substrate. The spacer comprised a 0.24 inchthick section of polycarbonate (Makronlon). The ignition assemblycomprised a FR-4 printed circuit board having a 0.03 inch diameteropening at the end to be disposed within an enclosure defined by thespacer and the substrates. A 0.0008 inch diameter Nichrome wire wassoldered to electrical conductors on the printed circuit board andpositioned across the opening. An initiator composition comprising 26.5%Al, 51.4% MoO₃, 7.7% B and 14.3% VITON® A500 weight percent wasdeposited onto the Nichrome wire and dried.

To assemble the thin film drug supply unit, the Nichrome wire comprisingthe initiator composition was positioned at one end of the solid fuelarea. A bead of epoxy (Epo-Tek 353 ND, Epoxy Technology) was applied toboth surfaces of the spacer, and the spacer, substrates and the ignitionassembly positioned and compressed. The epoxy was cured at a temperatureof 100° C. for 3 hours.

To ignite the solid fuel, a 0.4 Amp current was applied to theelectrical conductors connected to the Nichrome wire.

The airflow in the airway used for the measurements ranged from 14 L/minto 28 L/min corresponding to an airflow velocity of 1.5 m/sec and 3msec, respectively.

Measurements on such drug supply units demonstrated that the exteriorsurface of the substrate reached temperatures in excess of 400° C. inless than 150 milliseconds following activation of the initiator atwhich time the drug was completely thermally vaporized. The maximumpressure within the enclosure was less than 10 psig. In separatemeasurements, it was demonstrated that the enclosure was able towithstand a static pressure in excess of 60 psig at room temperature.The burn propagation speed across the expanse of solid fuel was measuredto be 25 cm/sec. The particulates forming the aerosol comprised greaterthan 95% of the drug, and greater than 90% of the drug originallydeposited on the substrates formed the aerosol.

Example 10 Measurement of Aerosol Purity and Yield

Drug supply units substantially as described in Example 9 andillustrated in FIGS. 10A and 10B were used to measure the percent yieldand percent purity of aerosols.

Two, 2×2 square inch, 0.004 inch thick 304 stainless steel foils formedthe substrates. A solid fuel comprising 76.16 wt % Zr, 19.04% MoO₃, 4.8%LAPONITE® RDS and water was coated onto the interior surface of thestainless steel substrates. The thickness of the solid fuel layer was0.0018±0.0003 inches. The layer of solid fuel covered an area of 1.69in² and after drying, the weight of the solid fuel disposed on theinterior surface of each substrate was 0.165 to 0.190 grams. An ˜6 μmthick thin film of a drug was deposited onto a 1.21 in² area of theexterior substrate surfaces using spray coating. The drug was dissolvedin a 15 mg/ml solution of isopropanol or acetone to facilitateprocessing. The thin film of drug was dried at ambient conditions and1.5 mg to 3.0 mg of drug was deposited on the exterior surface of eachsubstrate. The spacer comprised a 0.24 inch thick section ofpolycarbonate (Makronlon). The ignition assembly comprised a FR-4printed circuit board having a 0.03 inch diameter opening at the end tobe disposed within an enclosure defined by the spacer and thesubstrates. A 0.0008 inch diameter Nichrome wire was soldered toelectrical conductors on the printed circuit board and positioned acrossthe opening. An initiator composition comprising 26.5% Al, 51.4% MoO₃,7.7% B and 14.3% VITON® A500 weight percent was deposited onto theNichrome wire and dried.

To assemble the thin film drug supply unit, the Nichrome wire comprisingthe initiator composition was positioned at one end of the solid fuelarea. A bead of epoxy (Epo-Tek 353 ND, Epoxy Technology) was applied toboth surfaces of the spacer, and the spacer, substrates and the ignitionassembly positioned and compressed. The epoxy was cured at a temperatureof 100° C. for 3 hours.

To ignite the solid fuel, a 0.4 Amp current was applied to theelectrical conductors connected to the Nichrome wire.

The airflow in the airway used for the measurements ranged from 14 L/minto 28 L/min corresponding to an airflow velocity of 1.5 m/sec and 3msec, respectively.

After volatilization, the aerosol was captured on a mat forquantification of yield and analysis of purity. The quantity of materialrecovered on the mat was used to determine a percent yield, based on themass of drug coated onto the substrate. Any material deposited on thehousing or the remaining on the substrate was also recovered andquantified to determine a percent total recovery ((mass of drug on themat+mass of drug remaining on substrate and housing)/mass of drug coatedonto substrate). For compounds without UV absorption GC/MS or LC/MS wasused to quantify the recovery.

The percent purity was determined using HPLC UV absorption at 250 nm.However, as one of skill in the art recognizes, the purity of adrug-containing aerosol may be determined using a number of differentmethods. It should be noted that when the term “purity” is used, itrefers to the percentage of aerosol minus the percent byproduct producedin its formation. Byproducts for example, are those unwanted productsproduced during vaporization. For example, byproducts include thermaldegradation products as well as any unwanted metabolites of the activecompound or compounds. Examples of suitable methods for determiningaerosol purity are described in Sekine et al., Journal of ForensicScience 32:1271-1280 (1987) and in Martin et al., Journal of AnalyticToxicology 13:158-162 (1989).

One suitable method involves the use of a trap. In this method, theaerosol is collected in a trap in order to determine the percent orfraction of byproduct. Any suitable trap may be used. Suitable trapsinclude mats, glass wool, impingers, solvent traps, cold traps, and thelike. Mats are often most desirable. The trap is then typicallyextracted with a solvent, e.g. acetonitrile, and the extract subjectedto analysis by any of a variety of analytical methods known in the art,for example, gas, liquid, and high performance liquid chromatographyparticularly useful.

The gas or liquid chromatography method typically includes a detectorsystem, such as a mass spectrometry detector or an ultravioletabsorption detector. Ideally, the detector system allows determinationof the quantity of the components of the drug composition and of thebyproduct, by weight. This is achieved in practice by measuring thesignal obtained upon analysis of one or more known mass(es) ofcomponents of the drug composition or byproduct (standards) and thencomparing the signal obtained upon analysis of the aerosol to thatobtained upon analysis of the standard(s), an approach well known in theart.

In many cases, the structure of a byproduct may not be known or astandard for it may not be available. In such cases, one may calculatethe weight fraction of the byproduct by assuming it has an identicalresponse coefficient (e.g. for ultraviolet absorption detection,identical extinction coefficient) to the drug component or components inthe drug composition. When conducting such analysis, byproducts presentin less than a very small fraction of the drug compound, e.g. less than0.1% or 0.03% of the drug compound, are typically excluded. Because ofthe frequent necessity to assume an identical response coefficientbetween drug and byproduct in calculating a weight percentage ofbyproduct, it is often more desirable to use an analytical approach inwhich such an assumption has a high probability of validity. In thisrespect, high performance liquid chromatography with detection byabsorption of ultraviolet light at 225 nm is typically desirable. UVabsorption at 250 nm may be used for detection of compounds in caseswhere the compound absorbs more strongly at 250 nm or for other reasonsone skilled in the art would consider detection at 250 nm the mostappropriate means of estimating purity by weight using HPLC analysis. Incertain cases where analysis of the drug by UV are not viable, otheranalytical tools such as GC/MS or LC/MS may be used to determine purity.

Example 11 Preparation of Heating Unit with Percussion Ignition

The following procedure was used to prepare solid fuel coatingscomprising 76.16% Zr:19.04% MoO₃:4.8% LAPONITE® RDS.

To prepare wet Zirconium (Zr), the as-obtained suspension of Zr in DIwater (Chemetall, Germany) was agitated on a roto-mixer for 30 minutes.Ten to 40 mL of the wet Zr was dispensed into a 50 mL centrifuge tubeand centrifuged (Sorvall 6200RT) for 30 minutes at 3,200 rpm. The DIwater was removed to leave a wet Zr pellet.

To prepare a 15% LAPONITE® RDS solution, 85 grams of DI water was addedto a beaker. While stirring, 15 grams of LAPONITE® RDS (Southern ClayProducts, Gonzalez, Tex.) was added, and the suspension stirred for 30minutes.

The reactant slurry was prepared by first removing the wet Zr pellet aspreviously prepared from the centrifuge tube and placed in a beaker.Upon weighing the wet Zr pellet, the weight of dry Zr was determinedfrom the following equation: Dry Zr (g)=0.8234 (Wet Zr (g))−0.1059.

The amount of molybdenum trioxide to provide a 80:20 ratio of Zr to MoO₃was then determined, e.g, MoO₃=Dry Zr (g)/4, and the appropriate amountof MoO₃ powder (Accumet, N.Y.) was added to the beaker containing thewet Zr to produce a wet Zr:MoO₃ slurry. The amount of LAPONITE® RDS toobtain a final weight percent ratio of dry components of 76.16%Zr:19.04% MoO₃:4.80% LAPONITE® RDS was determined Excess water to obtaina reactant slurry comprising 40% DI water was added to the wet Zr andMoO₃ slurry. The reactant slurry was mixed for 5 minutes using an IKAUltra-Turrax mixing motor with a S25N-8G dispersing head (setting 4).The amount of 15% LAPONITE® RDS previously determined was then added tothe reactant slurry, and mixed for an additional 5 minutes using the IKAUltra-Turrax mixer. The reactant slurry was transferred to a syringe andstored for at least 30 minutes prior to coating.

The Zr:MoO₃:LAPONITE® RDS reactant slurry was then coated onto stainlesssteel foils. Stainless steel foils were first cleaned by sonication for5 minutes in a 3.2% by solution of Ridoline 298 in DI water at 60° C.Stainless steel foils were masked with 0.215 inch wide MYLAR® such thatthe center portion of each 0.004 inch thick 304 stainless steel foil wasexposed. The foils were placed on a vacuum chuck having 0.008 inch thickshims at the edges. Two (2) mL of the reactant slurry was placed at oneedge of the foil. Using a Sheen Auto-Draw Automatic Film Applicator 1137(Sheen Instruments) the reactant slurry was coated onto the foils bydrawing a #12 coating rod at an auto-draw coating speed of up to 50mm/sec across the surface of the foils to deposit approximately an 0.006inch thick layer of the Zr:MoO₃:LAPONITE® RDS reactant slurry. Thecoated foils were then placed in a 40° C. forced-air convection oven anddried for at least 2 hours. The masks were then removed from the foilsto leave a coating of solid fuel on the center section of each foil.

The ignition assembly comprised a thin stainless steel wire (wire anvil)dip coated ¼ an inch in an initiator composition comprising 620 parts byweight of titanium (size less than 20 μm), 100 part by weight ofpotassium chlorate, 180 parts by weight red phosphorus, 100 parts byweight sodium chlorate, and 620 parts by weight water with 2% polyvinylalcohol binder. The coated wire was then dried at about 40-50° C. for 1hour. The dried coated wire was placed into an ignition tube (softwalled aluminum tube 0.003 inch wall thickness) and one end was crimpedto hold the wire in place.

To assemble the heating unit, the ignition tube was place between twofuel coated foil substrates (fuel chips) with the open end of theignition tube aligned with the edge of the fuel coatings on the fuelchips. The fuel chips were sealed with aluminum adhesive tape.

To ignite the solid fuel, the ignition tube was struck with a brass rod.Both fuel chips in the heating unit readily ignited.

Example 12 An Embodiment of a Device with Multi-Heating Units UsingOptical Ignition

The following procedure was used to prepare solid fuel coatingscomprising 76.16% Zr:19.04% MoO₃:4.8% LAPONITE® RDS.

To prepare wet Zirconium (Zr), the as-obtained suspension of Zr in DIwater (Chemetall, Germany) was agitated on a roto-mixer for 30 minutes.Ten to 40 mL of the wet Zr was dispensed into a 50 mL centrifuge tubeand centrifuged (Sorvall 6200RT) for 30 minutes at 3,200 rpm. The DIwater was removed to leave a wet Zr pellet.

To prepare a 15% LAPONITE® RDS solution, 85 grams of DI water was addedto a beaker. While stirring, 15 grams of LAPONITE® RDS (Southern ClayProducts, Gonzalez, Tex.) was added, and the suspension stirred for 30minutes.

The reactant slurry was prepared by first removing the wet Zr pellet aspreviously prepared from the centrifuge tube and placed in a beaker.Upon weighing the wet Zr pellet, the weight of dry Zr was determinedfrom the following equation: Dry Zr (g)=0.8234 (Wet Zr (g))−0.1059.

The amount of molybdenum trioxide to provide a 80:20 ratio of Zr to MoO₃was then determined, e.g, MoO₃=Dry Zr (g)/4, and the appropriate amountof MoO₃ powder (Accumet, N.Y.) was added to the beaker containing thewet Zr to produce a wet Zr:MoO₃ slurry. The amount of LAPONITE® RDS toobtain a final weight percent ratio of dry components of 76.16%Zr:19.04% MoO₃:4.80% LAPONITE® RDS was determined Excess water to obtaina reactant slurry comprising 40% DI water was added to the wet Zr andMoO₃ slurry. The reactant slurry was mixed for 5 minutes using an IKAUltra-Turrax mixing motor with a S25N-8G dispersing head (setting 4).The amount of 15% LAPONITE® RDS previously determined was then added tothe reactant slurry, and mixed for an additional 5 minutes using the IKAUltra-Turrax mixer. The reactant slurry was transferred to a syringe andstored for at least 30 minutes prior to coating.

The Zr:MoO₃:LAPONITE® RDS reactant slurry was then coated onto 3 inchcircular stainless steel foils. Stainless steel foils were first cleanedby sonication for minutes in a 3.2% by solution of Ridoline 298 in DIwater at 60° C. Stainless steel foils 91 were masked with a 3 inch roundsheet of MYLAR® with twelve 0.25 inch by 0.5 inch spaces cut into theMYLAR® so that twelve rectangles of 0.25 by 0.5 inches of 0.004 inchthick 304 stainless steel foil was exposed. The foils were placed on avacuum chuck having 0.008 inch thick shims at the edges. Two (2) mL ofthe reactant slurry was placed at one edge of the foil. Using a SheenAuto-Draw Automatic Film Applicator 1137 (Sheen Instruments) thereactant slurry was coated onto the foils by drawing a #12 coating rodat an auto-draw coating speed of up to 50 mm/sec across the surface ofthe foils to deposit approximately an 0.006 inch thick layer of theZr:MoO₃:LAPONITE® RDS reactant slurry. The coated foils were then placedin a 40° C. forced-air convection oven and dried for at least 2 hours.The masks were then removed from the foils to leave twelve rectangularcoatings of solid fuel on each foil.

An initiator composition was prepared by adding 8.6 mL of a 4.25% VITON®A500/amyl acetate solution to a mixture of 0.680 g of Al (40-70 nm),1.320 g of MoO₃ (nano), and 0.200 g of boron (nano) and mixing well. Two1 iL drops of the initiator composition were placed in a 0.06 inchdiameter hole in the center of each of twelve 0.25 inch by 0.5 inchfiberglass mats (0.04 inch thickness, Directed Light). One drop ofinitiator composition was place in the hole from each side of fiberglassmat.

To assemble the heating unit, on the fuel coated foil (3 inch diameter)was placed four layers of double sided tape (3 inch diameter,Saint-Gobain Performance Plastics) with 12 rectangular holes (0.25 inchby 0.5 inch) cut into each tape such that the holes on the tape alignedwith the fuel coatings on the foils. Into each hole in the tape layerwas placed one fiberglass mat with the initiator. The tape was thencovered with a 3 inch circular window made out of clear plastic ( 1/16inch polycarbonate sheet, McMaster-Carr).

Each heating unit of the device was ignited is succession by pulsedflash light from a Xenon lamp powered by one AA battery through thepolycarbonate window.

Although the invention has been described with respect to particularembodiments, it will be apparent to those skilled in the art thatvarious changes and modifications can be made without departing from theinvention.

What is claimed is:
 1. A heating unit comprising: a) an enclosurecomprising at least one substrate having an exterior surface and aninterior surface, wherein the at least one substrate has a thickness inthe range of 0.001 to 0.020 inches; b) a layer of solid fuel disposedwithin the enclosure wherein the solid fuel layer has a thickness in therange of 0.001 to 0.030 inches and wherein the solid fuel is configuredto heat a portion of the exterior surface of the at least one substrateto a temperature of at least 200° C. within 3 seconds following ignitionof the solid fuel; and c) an igniter disposed at least partially withinthe enclosure for igniting the solid fuel.
 2. The heating unit of claim1 wherein within 1 second after ignition of the solid fuel, no more than10% of said area of the exterior surface has a temperature 50° C. to100° C. less than the remaining 90% of said area of the exteriorsurface.
 3. The heating unit of claim 1, wherein within 500 millisecondsafter ignition of the solid fuel, no more than 10% of said area of theexterior surface has a temperature 50° C. to 100° C. less than theremaining 90% of said area of the exterior surface.
 4. The heating unitof claim 1, wherein within 250 milliseconds after ignition of the solidfuel, no more than 10% of said area of the exterior surface has atemperature 50° C. to 100° C. less than the remaining 90% of said areaof the exterior surface.
 5. The heating unit of claim 1, wherein thethin layer of solid fuel has a thickness in the range of 0.001 to 0.005inches.
 6. The heating unit of claim 1, wherein the enclosure comprisesmore than one substrate.
 7. The heating unit of claim 1, wherein thesubstrate is a metal foil having a thickness in the range of 0.001 to0.010 inches.
 8. The heating unit of claim 1, wherein the solid fuelcomprises a metal reducing agent and a metal containing oxidizing agent.9. The heating unit of claim 8, wherein the metal containing oxidizingagent is selected from at least one of the following: MoO₃, KClO₄,KClO₃, and Fe₂O₃.
 10. The heating unit of claim 8, wherein the metalreducing agent is selected from at least one of the following: aluminum,zirconium, iron, and titanium.
 11. The heating unit of claim 8, whereinthe amount of metal reducing agent comprises from 60% to 90% by weightof the total dry weight of the solid fuel.
 12. The heating unit of claim8, wherein the amount of metal reducing agent comprises from 10% to 40%by weight of the total dry weight of the solid fuel.
 13. The heatingunit of claim 1, wherein the solid fuel comprises at least one additivematerial.
 14. The heating unit of claim 13, wherein the additivematerial is selected from at least one of the following: a clay gellingagent, nitrocellulose, polyvinylalcohol, diatomaceous earthy glass beadsand a colloidal silica.
 15. The heating unit of claim 7, wherein thesubstrate has a thickness in the range of 0.002 to 0.010 inches.
 16. Theheating unit of claim 7, wherein the substrate has a thickness in therange of 0.002 to 0.005 inches.
 17. The heating unit of claim 1, whereinthe substrate is a metal, an alloy, or a ceramic.
 18. The heating unitof claim 1 wherein the igniter comprises: an optical window in theenclosure; and a light sensitive initiator composition disposed withinthe enclosure.
 19. The heating unit of claim 18, where the initiatorcomposition comprises a reducing agent and an oxidizing agent.
 20. Theheating unit of claim 19, wherein the reducing agent of the initiatorcomposition is selected from at least one of the following: zirconium,titanium, and aluminum.
 21. The heating unit of claim 19, wherein theoxidizing agent of the initiator composition is selected from at leastone of the following: molybdenum trioxide, potassium perchlorate, copperoxide, and tungsten trioxide.
 22. The heating unit of claim 18, whereinthe initiator composition comprises aluminum, boron, molybdenumtrioxide, and a clay gelling agent.
 23. The heating unit of claim 1,wherein the substrate comprises a multi-layer structure.
 24. The heatingunit of claim 1, wherein substrate is a polyimide, a polyester, or afluoropolymer.
 25. The heating unit of claim 1, wherein the igniter is apercussive igniter.
 26. The heating unit of claim 25, further comprisingat least one impulse absorbing material disposed within the enclosure.27. The heating unit of claim 25, further comprising a spacer providingan empty volume within the enclosure.
 28. The heating unit of claim 1,wherein at the least one substrate is a metal, an alloy, or a ceramic.29. The heating unit of claim 1, wherein the enclosure is capable ofwithstanding an internal pressure of at least 50 psig.
 30. The heatingunit of claim 1, further comprising a drug layer on a portion of theexterior surface of the at least one substrate.